Certain triazolopyridines and triazolopyrazines, compositions thereof and methods of use therefor

ABSTRACT

Provided are certain triazolopyridines and triazolopyrazines, compositions thereof and methods of use therefor.

This application is a 35 U.S.C. §371 national stage filing ofInternational Application No. PCT/CN2010/080499, filed Dec. 30, 2010,and claims priority to PCT/CN2009/076321, filed Dec. 31, 2009, entitled“CERTAIN TRIAZOLOPYRIDINES AND TRIAZOLOPYRAZINES, COMPOSITIONS THEREOFAND METHODS OF USE THEREFOR”, the contents of which are herebyincorporated by reference.

The c-Met protein, also known as the hepatocyte growth factor (HGF)receptor, is a transmembrane 190 kDa heterodimer with tyrosine kinaseactivity, encoded by the c-met oncogene. The HGF/c-Met signallingpathway has been shown to demonstrate various cellular responses,including mitogenic, proliferative, morphogenic and angiogenicactivities. The inhibition of the HGF/c-Met pathway has significantpotential for the treatment of cancer.

Provided is at least one compound of formula 1:

and/or at least one pharmaceutically acceptable salt thereof wherein

-   X is N, Y is selected from —O—, —S—, and —N(R⁷)— and R¹ is selected    from aryl and heteroaryl, each of which is optionally substituted    with one or more groups selected from halo, —CF₃, —CF₂H, cycloalkyl,    —C(O)R¹¹, —C(O)OR¹¹, —CN, —C(O)NR¹³R¹⁴, —NR¹³R¹⁴, —NR¹³C(O)R¹¹,    —NR¹³S(O)_(n)R¹², —NR¹³S(O)_(n)NR¹³R¹⁴, —NR¹³C(O)OR¹²,    —NR¹³C(O)NR¹³R¹⁴, —NO₂, —S(O)_(n)R¹², —S(O)_(n)NR¹³R¹⁴, heterocycle,    heteroaryl, aryl, alkenyl, alkynyl, lower alkyl, lower alkyl    substituted with hydroxy, lower alkyl substituted with lower alkoxy,    lower alkyl substituted with —NR¹³R¹⁴, and lower alkyl substituted    with heterocycle; or-   X is N, Y is absent and R¹ is a fused bicyclic heteroaryl optionally    substituted with one or more groups selected from halo, —CF₃, —CF₂H,    cycloalkyl, —C(O)R¹¹, —C(O)OR¹¹, —CN, —C(O)NR¹³R¹⁴, —NR¹³R¹⁴,    —NR¹³C(O)R¹¹, —NR¹³S(O)_(n)R¹², —NR¹³S(O)_(n)NR¹³R¹⁴, —NR¹³C(O)OR¹²,    —NR¹³C(O)NR¹³R¹⁴, —NO₂, —S(O)_(n)NR¹³R¹⁴, heterocycle, heteroaryl,    aryl, alkenyl, alkynyl, lower alkyl, lower alkyl substituted with    hydroxy, lower alkyl substituted with lower alkoxy, lower alkyl    substituted with —NR¹³R¹⁴, and lower alkyl substituted with    heterocycle; or-   X is C(R⁶), Y is selected from —O—, —S—, and —N(R⁷)— or Y is absent,    and R¹ is heteroaryl optionally substituted with one or more groups    selected from halo, —CF₃, —CF₂H, cycloalkyl, —C(O)R¹¹, —C(O)OR¹¹,    —CN, —C(O)NR¹³R¹⁴, —NR¹³R¹⁴, —NR¹³C(O)R¹¹, —NR¹³S(O)_(n)R¹²,    —NR¹³S(O)_(n)NR¹³R¹⁴, —NR¹³C(O)OR¹², —NR¹³C(O)NR¹³R¹⁴, —NO₂,    —S(O)_(n)R¹², —S(O)_(n)NR¹³R¹⁴, heterocycle, heteroaryl, aryl,    alkenyl, alkynyl, lower alkyl, lower alkyl substituted with hydroxy,    lower alkyl substituted with lower alkoxy, lower alkyl substituted    with —NR¹³R¹⁴, and lower alkyl substituted with heterocycle;-   R² and R³ are independently selected from hydrogen and alkyl, or R²    and R³, together with the carbon to which they are attached, form a    ring chosen from 3- to 7-membered cycloalkyl and 3- to 7-membered    heterocycle;-   R⁴ is selected from halo, alkyl, cycloalkyl, heterocycle, aryl and    heteroaryl, each of which, except for halo, is optionally    substituted with one or more groups selected from    -   lower alkyl optionally substituted with one or more groups        selected from hydroxy, lower alkoxy, cyano, halo, —C(O)OR¹¹,        —C(O)NR¹³R¹⁴, —NR¹³R¹⁴, —OC(O)R¹¹, —NR¹³C(O)R¹¹,        —NR¹³S(O)_(n)R¹², —NR¹³S(O)_(n)NR¹³R¹⁴, —NR¹³C(O)OR¹², and        —NR¹³C(O)NR¹³R¹⁴,    -   lower alkoxy optionally substituted with one or more groups        selected from halo, hydroxy, and lower alkoxy,    -   cycloalkoxy optionally substituted with one or more groups        selected from halo, hydroxy, and lower alkoxy,    -   heterocycloalkoxy optionally substituted with one or more groups        selected from halo, hydroxy, and lower alkoxy,    -   heterocycle optionally substituted with one or more groups        selected from lower alkyl, halo, hydroxy, and lower alkoxy,    -   heteroaryloxy optionally substituted with one or more groups        selected from lower alkyl, halo, hydroxy, and lower alkoxy,    -   aryl optionally substituted with one or more groups selected        from lower alkyl, halo, hydroxy, and lower alkoxy,    -   heteroaryl optionally substituted with one or more groups        selected from lower alkyl, halo, hydroxy, and lower alkoxy,    -   halo, cyano, —C(O)R¹¹, —C(O)OR¹¹, —NR¹³R¹⁴, —NR¹³C(O)R¹¹,        —NR¹³S(O)_(n)R¹², NR¹³S(O)_(n)NR¹³R¹⁴, —NR¹³C(O)OR¹²,        —NR¹³C(O)NR¹³R¹⁴, —C(O)NR¹³R¹⁴, —S(O)_(n)R¹², and        —S(O)_(n)NR¹³R¹⁴;-   R⁵ is selected from hydrogen, halo, OH, NH₂, CF₃, —CF₂H, alkyl,    alkenyl, and alkynyl;-   R⁶ is selected from hydrogen, —OH, —NH₂, —NHC(O)R¹¹, halo and alkyl;-   R⁷ is selected from hydrogen and lower alkyl;-   each n is independently 0, 1, or 2;-   R¹¹, R¹², R¹³, and R¹⁴ are independently selected from hydrogen,    alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and    heterocycle, each of which except for hydrogen, is optionally    substituted with one or more groups selected from halo, lower alkyl,    hydroxy, and lower alkoxy, or R¹³ and R¹⁴, with the nitrogen to    which they are attached, combine to form a heterocycle ring, which    is optionally substituted with one or more groups selected from    halo, lower alkyl, hydroxy, and lower alkoxy and further optionally    includes one or two additional heteroatoms in the heterocycle ring    wherein the one or two additional heteroatoms are selected from —O—,    —S—, and —N(R¹⁵)—; and-   R¹⁵ is selected from hydrogen, lower alkyl, —C(O)R¹¹, —C(O)OR¹¹,    —C(O)NR¹³R¹⁴, —S(O)_(n)R¹², and —S(O)_(n)NR¹³R¹⁴    provided that-   R¹ is not optionally substituted phenyl or optionally substituted    4-pyridinyl;-   when X is N, R² is hydrogen or methyl, R³ and R⁵ are hydrogen, and Y    is absent, then R¹ is not quinolin-6-yl, 7-fluoroquinolin-6-yl,    3-quinazolin-6-yl, 2-3-dihydro-benzofuran-5-yl, or    2,3-dihydro-benzo[1,4]dioxin-6-yl; and-   when X is N, R², R³ and R⁵ are hydrogen, and Y is —O— or —N(R⁷)—,    and R¹ is quinolin-6-yl, 7-fluoroquinolin-6-yl, 3-quinazolin-6-yl,    2-3-dihydro-benzofuran-5-yl, or 2,3-dihydro-benzo[1,4]dioxin-6-yl;    then R⁴ is optionally substituted heteroaryl.

Also provided is a composition comprising at least one compound and/orat least one pharmaceutically acceptable salt described herein and atleast one pharmaceutically acceptable carrier.

Also provided is a method of inhibiting the activity of c-Met comprisingcontacting the receptor with an effective amount of at least onecompound and/or at least one pharmaceutically acceptable salt describedherein.

Also provided is a method of treating cancer responsive to inhibition ofc-Met comprising administering to a subject in need thereof an effectiveamount of at least one compound and/or at least one pharmaceuticallyacceptable salt described herein.

As used in the present specification, the following words, phrases andsymbols are generally intended to have the meanings as set forth below,except to the extent that the context in which they are used indicatesotherwise. The following abbreviations and terms have the indicatedmeanings throughout:

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —CONH₂ isattached through the carbon atom.

The term “alkyl” herein refers to a straight or branched hydrocarbon,containing 1-10 carbon atoms. Examples of alkyl groups include, but arenot limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, andt-butyl. “Lower alkyl” refers to a straight or branched hydrocarbon,containing 1-4 carbon atoms.

By “alkoxy” is meant a straight or branched alkyl group of the indicatednumber of carbon atoms attached through an oxygen bridge such as, forexample, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy,tert-butoxy, pentoxy, 2-pentyloxy, isopentoxy, neopentoxy, hexoxy,2-hexoxy, 3-hexoxy, 3-methylpentoxy, and the like. Alkoxy groups willusually have from 1 to 6 carbon atoms attached through the oxygenbridge. “Lower alkoxy” refers to a straight or branched alkoxy, whereinthe alkyl portion contains 1-4 carbon atoms.

The term “alkenyl” herein refers to a C₂₋₁₀ straight or branchedhydrocarbon, containing one or more C═C double bonds. Examples ofalkenyl groups include, but are not limited to, vinyl, 2-propenyl, and2-butenyl.

The term “alkynyl” herein refers to a C₂₋₁₀ straight or branchedhydrocarbon, containing one or more C≡C triple bonds. Examples ofalkynyl groups include, but are not limited to, ethynyl, 2-propynyl, and2-butynyl.

The term “cycloalkyl” refers to a saturated and partially unsaturatedcyclic hydrocarbon group having 3 to 12 carbons. Examples of cycloalkylgroups include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, andcyclooctyl. The ring may be saturated or have one or more double bonds(i.e. partially unsaturated), but not fully conjugated.

“Aryl” encompasses:

-   -   5- and 6-membered carbocyclic aromatic rings, for example,        benzene;    -   bicyclic ring systems wherein at least one ring is carbocyclic        and aromatic, for example, naphthalene, indane, and        1,2,3,4-tetrahydroquinoline; and    -   tricyclic ring systems wherein at least one ring is carbocyclic        and aromatic, for example, fluorene.

For example, aryl includes 5- and 6-membered carbocyclic aromatic ringsfused to a 5- to 7-membered heterocyclic ring containing one or moreheteroatoms selected from N, O, and S, provided that the point ofattachment is at the carbocyclic aromatic ring. Bivalent radicals formedfrom substituted benzene derivatives and having the free valences atring atoms are named as substituted phenylene radicals. Bivalentradicals derived from univalent polycyclic hydrocarbon radicals whosenames end in “-yl” by removal of one hydrogen atom from the carbon atomwith the free valence are named by adding “-idene” to the name of thecorresponding univalent radical, e.g., a naphthyl group with two pointsof attachment is termed naphthylidene. Aryl, however, does not encompassor overlap in any way with heteroaryl, separately defined below. Hence,if one or more carbocyclic aromatic rings are fused with a heterocyclicaromatic ring, the resulting ring system is heteroaryl, not aryl, asdefined herein.

The term “halo” includes fluoro, chloro, bromo, and iodo, and the term“halogen” includes fluorine, chlorine, bromine, and iodine.

The term “heteroaryl” refers to

-   -   5- to 8-membered aromatic, monocyclic rings containing one or        more, for example, from 1 to 4, or, in some embodiments, from 1        to 3, heteroatoms selected from N, O, and S, with the remaining        ring atoms being carbon;    -   8- to 12-membered bicyclic rings containing one or more, for        example, from 1 to 4, or, in some embodiments, from 1 to 3,        heteroatoms selected from N, O, and S, with the remaining ring        atoms being carbon and wherein at least one heteroatom is        present in an aromatic ring; and    -   11- to 14-membered tricyclic rings containing one or more, for        example, from 1 to 4, or in some embodiments, from 1 to 3,        heteroatoms selected from N, O, and S, with the remaining ring        atoms being carbon and wherein at least one heteroatom is        present in an aromatic ring.

For example, heteroaryl includes a 5- to 7-membered heterocyclicaromatic ring fused to a 5- to 7-membered cycloalkyl ring. For suchfused, bicyclic heteroaryl ring systems wherein only one of the ringscontains one or more heteroatoms, the point of attachment may be at theheteroaromatic ring or the cycloalkyl ring.

When the total number of S and O atoms in the heteroaryl group exceeds1, those heteroatoms are not adjacent to one another. In someembodiments, the total number of S and O atoms in the heteroaryl groupis not more than 2. In some embodiments, the total number of S and Oatoms in the aromatic heterocycle is not more than 1.

Examples of heteroaryl groups include, but are not limited to, (asnumbered from the linkage position assigned priority 1), 2-pyridyl,3-pyridyl, 4-pyridyl, 2,3-pyrazinyl, 3,4-pyrazinyl, 2,4-pyrimidinyl,3,5-pyrimidinyl, 1-pyrazolyl, 2,3-pyrazolyl, 2,4-imidazolinyl,isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, thienyl,benzothienyl, furyl, benzofuryl, benzoimidazolinyl, indolinyl,pyridizinyl, triazolyl, quinolinyl, pyrazolyl, and5,6,7,8-tetrahydroisoquinoline.

Bivalent radicals derived from univalent heteroaryl radicals whose namesend in “-yl” by removal of one hydrogen atom from the atom with the freevalence are named by adding “-idene” to the name of the correspondingunivalent radical, e.g., a pyridyl group with two points of attachmentis a pyridylidene. Heteroaryl does not encompass or overlap with aryl asdefined above.

Substituted heteroaryl also includes ring systems substituted with oneor more oxide (—O⁻) substituents, such as pyridinyl N-oxides.

By “heterocycle” is meant a single aliphatic ring, usually with 3 to 7ring atoms, containing at least 2 carbon atoms in addition to 1-3heteroatoms independently selected from oxygen, sulfur, and nitrogen, aswell as combinations comprising at least one of the foregoingheteroatoms. “Heterocycle” also refers to 5- to 7-membered heterocyclicring containing one or more heteroatoms selected from N, O, and S fusedwith 5- and 6-membered carbocyclic aromatic ring, provided that thepoint of attachment is at the heterocyclic ring. The rings may besaturated or have one or more double bonds (i.e. partially unsaturated).The heterocycle can be substituted by oxo. The point of the attachmentmay be carbon or heteroatom in the heterocyclic ring.

Suitable heterocycles include, for example (as numbered from the linkageposition assigned priority 1), 1-pyrrolidinyl, 2-pyrrolidinyl,2,4-imidazolidinyl, 2,3-pyrazolidinyl, 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-piperidinyl, and 2,5-piperazinyl. Morpholinyl groupsare also contemplated, including 2-morpholinyl and 3-morpholinyl(numbered wherein the oxygen is assigned priority 1). Substitutedheterocycle also includes ring systems substituted with one or more oxomoieties, such as piperidinyl N-oxide, morpholinyl-N-oxide,1-oxo-1-thiomorpholinyl and 1,1-dioxo-1-thiomorpholinyl.

By “optional” or “optionally” is meant that the subsequently describedevent or circumstance may or may not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not. For example, “optionally substituted alkyl”encompasses both “alkyl” and “substituted alkyl” as defined below. Itwill be understood by those skilled in the art, with respect to anygroup containing one or more substituents, that such groups are notintended to introduce any substitution or substitution patterns that aresterically impractical, synthetically non-feasible and/or inherentlyunstable.

The term “substituted”, as used herein, means that any one or morehydrogens on the designated atom or group is replaced with a selectionfrom the indicated group, provided that the designated atom's normalvalence is not exceeded. When a substituent is oxo (i.e., ═O) then 2hydrogens on the atom are replaced. Combinations of substituents and/orvariables are permissible only if such combinations result in stablecompounds or useful synthetic intermediates. A stable compound or stablestructure is meant to imply a compound that is sufficiently robust tosurvive isolation from a reaction mixture, and subsequent formulation asan agent having at least practical utility. Unless otherwise specified,substituents are named into the core structure. For example, it is to beunderstood that when (cycloalkyl)alkyl is listed as a possiblesubstituent, the point of attachment of this substituent to the corestructure is in the alkyl portion.

In some embodiments, “substituted with one or more groups” refers to twohydrogens on the designated atom or group being independently replacedwith two selections from the indicated group of substituents. In someembodiments, “substituted with one or more groups” refers to threehydrogens on the designated atom or group being independently replacedwith three selections from the indicated group of substituents. In someembodiments, “substituted with one or more groups” refers to fourhydrogens on the designated atom or group being independently replacedwith four selections from the indicated group of substituents.

Compounds described herein include, but are not limited to, theiroptical isomers, racemates, and other mixtures thereof. In thosesituations, the single enantiomers or diastereomers, i.e., opticallyactive forms, can be obtained by asymmetric synthesis or by resolutionof the racemates or mixtures of diastereomers. Resolution of theracemates or mixtures of diastereomers can be accomplished, for example,by conventional methods such as crystallization in the presence of aresolving agent, or chromatography, using, for example a chiralhigh-pressure liquid chromatography (HPLC) column. In addition, suchcompounds include Z- and E-forms (or cis- and trans-forms) of compoundswith carbon-carbon double bonds. Where compounds described herein existin various tautomeric forms, the term “compound” is intended to includeall tautomeric forms of the compound. Such compounds also includecrystal forms including polymorphs and clathrates. Similarly, the term“salt” is intended to include all isomers, racemates, other mixtures, Z-and E-forms, tautomeric forms and crystal forms of the salt of thecompound.

“Pharmaceutically acceptable salts” include, but are not limited tosalts with inorganic acids, such as hydrochlorate, phosphate,diphosphate, hydrobromate, sulfate, sulfinate, nitrate, and like salts;as well as salts with an organic acid, such as malate, maleate,fumarate, tartrate, succinate, citrate, acetate, lactate,methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate,salicylate, stearate, and alkanoate such as acetate, HOCC—(CH₂)_(n)—COOHwhere n is 0-4, and like salts. Similarly, pharmaceutically acceptablecations include, but are not limited to sodium, potassium, calcium,aluminum, lithium, and ammonium.

In addition, if a compound described herein is obtained as an acidaddition salt, the free base can be obtained by basifying a solution ofthe acid salt. Conversely, if the product is a free base, an additionsalt, particularly a pharmaceutically acceptable addition salt, may beproduced by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds. Thoseskilled in the art will recognize various synthetic methodologies thatmay be used to prepare non-toxic pharmaceutically acceptable additionsalts.

A “solvate,” such as a “hydrate,” is formed by the interaction of asolvent and a compound. The term “compound” is intended to includesolvates, including hydrates, of compounds. Similarly, “salts” includessolvates, such as hydrates, of salts. Suitable solvates arepharmaceutically acceptable solvates, such as hydrates, includingmonohydrates and hemi-hydrates.

A “chelate” is formed by the coordination of a compound to a metal ionat two (or more) points. The term “compound” is intended to includechelates of compounds. Similarly, “salts” includes chelates of salts.

A “non-covalent complex” is formed by the interaction of a compound andanother molecule wherein a covalent bond is not formed between thecompound and the molecule. For example, complexation can occur throughvan der Waals interactions, hydrogen bonding, and electrostaticinteractions (also called ionic bonding). Such non-covalent complexesare included in the term “compound’.

The term “hydrogen bond” refers to a form of association between anelectronegative atom (also known as a hydrogen bond acceptor) and ahydrogen atom attached to a second, relatively electronegative atom(also known as a hydrogen bond donor). Suitable hydrogen bond donor andacceptors are well understood in medicinal chemistry (G. C. Pimentel andA. L. McClellan, The Hydrogen Bond, Freeman, San Francisco, 1960; R.Taylor and O. Kennard, “Hydrogen Bond Geometry in Organic Crystals”,Accounts of Chemical Research, 17, pp. 320-326 (1984)).

As used herein the terms “group”, “radical” or “fragment” are synonymousand are intended to indicate functional groups or fragments of moleculesattachable to a bond or other fragments of molecules.

The term “active agent” is used to indicate a chemical substance whichhas biological activity. In some embodiments, an “active agent” is achemical substance having pharmaceutical utility.

“Treating” or “treatment” or “alleviation” refers to administering atleast one compound and/or at least one pharmaceutically acceptable saltdescribed herein to a subject that has cancer, or has a symptom ofcancer, or has a predisposition toward cancer, with the purpose to cure,heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affectcancer, the symptoms of cancer, or the predisposition toward cancer.

The term “effective amount” refers to an amount of at least one compoundand/or at least one pharmaceutically acceptable salt described hereineffective to “treat” a disease or disorder in a subject. In the case ofcancer, the effective amount may cause any of the changes observable ormeasurable in a subject as described in the definition of “treating,”“treatment” and “alleviation” above. For example, the effective amountcan reduce the number of cancer or tumor cells; reduce the tumor size;inhibit or stop tumor cell infiltration into peripheral organsincluding, for example, the spread of tumor into soft tissue and bone;inhibit and stop tumor metastasis; inhibit and stop tumor growth;relieve to some extent one or more of the symptoms associated with thecancer, reduce morbidity and mortality; improve quality of life; or acombination of such effects. An effective amount may be an amountsufficient to decrease the symptoms of a disease responsive toinhibition of c-Met activity. For cancer therapy, efficacy in vivo can,for example, be measured by assessing the duration of survival, time todisease progression (TTP), the response rates (RR), duration ofresponse, and/or quality of life. Effective amounts may vary, asrecognized by those skilled in the art, depending on route ofadministration, excipient usage, and co-usage with other agents.

The term “inhibition” indicates a decrease in the baseline activity of abiological activity or process. “Inhibition of c-Met activity” refers toa decrease in the activity of c-Met as a direct or indirect response tothe presence of at least one at least one compound and/or at least onepharmaceutically acceptable salt described herein, relative to theactivity of c-Met in the absence of the at least one compound and/or theat least one pharmaceutically acceptable salt thereof. The decrease inactivity may be due to the direct interaction of the at least onecompound and/or at least one pharmaceutically acceptable salt describedherein with c-Met, or due to the interaction of the at least onecompound and/or at least one pharmaceutically acceptable salt describedherein, with one or more other factors that in turn affect c-Metactivity. For example, the presence of at least one compound and/or atleast one pharmaceutically acceptable salt described herein, maydecrease c-Met activity by directly binding to the c-Met, by causing(directly or indirectly) another factor to decrease c-Met activity, orby (directly or indirectly) decreasing the amount of c-Met present inthe cell or organism.

The details of one or more embodiments of the invention are set forthbelow.

Provided is at least one compound of formula 1:

and/or at least one pharmaceutically acceptable salt thereof wherein

-   X is N, Y is selected from —O—, —S—, and —N(R⁷)— and R¹ is selected    from aryl and heteroaryl, each of which is optionally substituted    with one or more groups selected from halo, —CF₃, —CF₂H, cycloalkyl,    —C(O)R¹¹, —C(O)OR¹¹, —CN, —C(O)NR¹³R¹⁴, —NR¹³R¹⁴, —NR¹³C(O)R¹¹,    —NR¹³S(O)_(n)R¹², —NR¹³S(O)_(n)NR¹³R¹⁴, —NR¹³C(O)OR¹²,    —NR¹³C(O)NR¹³R¹⁴, —NO₂, —S(O)_(n)R¹², —S(O)_(n)NR¹³R¹⁴, heterocycle,    heteroaryl, aryl, alkenyl, alkynyl, lower alkyl, lower alkyl    substituted with hydroxy, lower alkyl substituted with lower alkoxy,    lower alkyl substituted with —NR¹³R¹⁴, and lower alkyl substituted    with heterocycle; or-   X is N, Y is absent and R¹ is a fused bicyclic heteroaryl optionally    substituted with one or more groups selected from halo, —CF₃, —CF₂H,    cycloalkyl, —C(O)R¹¹, —C(O)OR¹¹, —CN, —C(O)NR¹³R¹⁴, —NR¹³R¹⁴,    —NR¹³C(O)R¹¹, —NR¹³S(O)_(n)R¹², —NR¹³S(O)_(n)NR¹³R¹⁴, —NR¹³C(O)OR¹²,    —NR¹³C(O)NR¹³R¹⁴, —NO₂, —S(O)_(n)R¹², —S(O)_(n)NR¹³R¹⁴, heterocycle,    heteroaryl, aryl, alkenyl, alkynyl, lower alkyl, lower alkyl    substituted with hydroxy, lower alkyl substituted with lower alkoxy,    lower alkyl substituted with —NR¹³R¹⁴, and lower alkyl substituted    with heterocycle; or-   X is C(R⁶), Y is selected from —O—, —S—, and —N(R⁷)— or Y is absent,    and R¹ is heteroaryl optionally substituted with one or more groups    selected from halo, —CF₃, —CF₂H, cycloalkyl, —C(O)R¹¹, —C(O)OR¹¹,    —CN, —C(O)NR¹³R¹⁴, —NR¹³R¹², —NR¹³C(O)R¹¹, —NR¹³S(O)_(n)R¹²,    —NR¹³S(O)_(n)NR¹³R¹⁴, —NR¹³C(O)OR¹², —NR¹³C(O)NR¹³R¹⁴, —NO₂,    —S(O)_(n)NR¹³R¹⁴, heterocycle, heteroaryl, aryl, alkenyl, alkynyl,    lower alkyl, lower alkyl substituted with hydroxy, lower alkyl    substituted with lower alkoxy, lower alkyl substituted with    —NR¹³R¹⁴, and lower alkyl substituted with heterocycle;-   R² and R³ are independently selected from hydrogen and alkyl, or R²    and R³, together with the carbon to which they are attached, form a    ring chosen from 3- to 7-membered cycloalkyl and 3- to 7-membered    heterocycle;-   R⁴ is selected from halo, alkyl, cycloalkyl, heterocycle, aryl and    heteroaryl, each of which, except for halo, is optionally    substituted with one or more groups selected from    -   lower alkyl optionally substituted with one or more groups        selected from hydroxy, lower alkoxy, cyano, halo, —C(O)OR¹¹,        —C(O)NR¹³R¹⁴, NR¹³R¹⁴, —OC(O)R¹¹, —NR¹³C(O)R¹¹,        —NR¹³S(O)_(n)R¹², —NR¹³S(O)_(n)NR¹³R¹⁴, —NR¹³C(O)OR¹², and        —NR¹³C(O)NR¹³R¹⁴,    -   lower alkoxy optionally substituted with one or more groups        selected from halo, hydroxy, and lower alkoxy,    -   cycloalkoxy optionally substituted with one or more groups        selected from halo, hydroxy, and lower alkoxy,    -   heterocycloalkoxy optionally substituted with one or more groups        selected from halo, hydroxy, and lower alkoxy,    -   heterocycle optionally substituted with one or more groups        selected from lower alkyl, halo, hydroxy, and lower alkoxy,    -   heteroaryloxy optionally substituted with one or more groups        selected from lower alkyl, halo, hydroxy, and lower alkoxy,    -   aryl optionally substituted with one or more groups selected        from lower alkyl, halo, hydroxy, and lower alkoxy,    -   heteroaryl optionally substituted with one or more groups        selected from lower alkyl, halo, hydroxy, and lower alkoxy,    -   halo, cyano, —C(O)R¹¹, —C(O)OR¹¹, —NR¹³R¹⁴, —NR¹³C(O)R¹¹,        —NR¹³S(O)_(n)R¹², —NR¹³S(O)nNR¹³R¹⁴, —NR¹³C(O)OR¹²,        —NR¹³C(O)NR¹³R¹⁴, —C(O)NR¹³R¹⁴, —S(O)_(n)R¹², and        —S(O)_(n)NR¹³R¹⁴;-   R⁵ is selected from hydrogen, halo, OH, NH₂, CF₃, —CF₂H, alkyl,    alkenyl, and alkynyl;-   R⁶ is selected from hydrogen, —OH, —NH₂, —NHC(O)R¹¹, halo and alkyl;-   R⁷ is selected from hydrogen and lower alkyl;-   each n is independently 0, 1, or 2;-   R¹¹, R¹², R¹³, and R¹⁴ are independently selected from hydrogen,    alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and    heterocycle, each of which except for hydrogen, is optionally    substituted with one or more groups selected from halo, lower alkyl,    hydroxy, and lower alkoxy, or R¹³ and R¹⁴, with the nitrogen to    which they are attached, combine to form a heterocycle ring, which    is optionally substituted with one or more groups selected from    halo, lower alkyl, hydroxy, and lower alkoxy and further optionally    includes one or two additional heteroatoms in the heterocycle ring    wherein the one or two additional heteroatoms are selected from —O—,    —S—, and —N(R¹⁵)—; and-   R¹⁵ is selected from hydrogen, lower alkyl, —C(O)R¹¹, —C(O)OR¹¹,    —C(O)NR¹³R¹⁴, —S(O)_(n)R¹², and —S(O)_(n)NR¹³R¹⁴-   provided that-   R¹ is not optionally substituted phenyl or optionally substituted    4-pyridinyl;-   when X is N, R² is hydrogen or methyl, R³ and R⁵ are hydrogen, and Y    is absent, then R¹ is not quinolin-6-yl, 7-fluoroquinolin-6-yl,    3-quinazolin-6-yl, 2-3-dihydro-benzofuran-5-yl, or    2,3-dihydro-benzo[1,4]dioxin-6-yl; and-   when X is N, R², R³ and R⁵ are hydrogen, and Y is —O— or —N(R⁷)—,    and R¹ is quinolin-6-yl, 7-fluoroquinolin-6-yl, 3-quinazolin-6-yl,    2-3-dihydro-benzofuran-5-yl, or 2,3-dihydro-benzo[1,4]dioxin-6-yl;    then R⁴ is optionally substituted heteroaryl.

In some embodiments, X is N. In some embodiments, X is C(R⁶). In someembodiments, R⁶ is selected from hydrogen, halo and lower alkyl. In someembodiments, R⁶ is hydrogen.

In some embodiments, Y is —O—. In some embodiments, Y is —S—. In someembodiments, Y is —N(R⁷)—. In some embodiments, R⁷ is hydrogen ormethyl. In some embodiments, R⁷ is hydrogen. In some embodiments, Y isabsent.

In some embodiments, R¹ is 8-10 membered heteroaryl optionallysubstituted with one or more groups selected from halo, —CF₃, —CF₂H,cycloalkyl, —C(O)R¹¹, —C(O)OR¹¹, —CN, —C(O)NR¹³R¹⁴, —NR¹³R¹⁴,—NR¹³C(O)R¹¹, —NR¹³S(O)_(n)R¹², —NR¹³R¹⁴, —NR¹³C(O)NR¹³C(O)OR¹²,—NR¹³C(O)NR¹³R¹⁴, —NO₂, —S(O)_(n)R¹², —S(O)_(n)NR¹³R¹⁴, heterocycle,heteroaryl, aryl, alkenyl, alkynyl, lower alkyl, lower alkyl substitutedwith hydroxy, lower alkyl substituted with lower alkoxy, lower alkylsubstituted with —NR¹³R¹⁴, and lower alkyl substituted with heterocycle.In some embodiments, R¹ is 8-10 membered heteroaryl optionallysubstituted with one or more groups selected from halo, lower alkyl,lower alkyl substituted with hydroxy, and lower alkyl substituted withlower alkoxy.

In some embodiments, R¹ is selected from quinolin-6-yl,thieno[3,2-c]pyridin-2-yl, benzo[d]thiazol-6-yl, andimidazo[1,2-a]pyridin-6-yl, each of which is optionally substituted withone or more groups selected from halo, lower alkyl, lower alkylsubstituted with hydroxy, and lower alkyl substituted with lower alkoxy.In some embodiments, R¹ is selected from quinolin-6-yl optionallysubstituted with one or more groups selected from halo, lower alkyl,lower alkyl substituted with hydroxy, and lower alkyl substituted withlower alkoxy.

In some embodiments, R¹ is a ring system selected from

wherein each of said ring systems is optionally substituted with one ormore groups selected from halo, CF₃, —CF₂H, cycloalkyl, —C(O)R¹¹,C(O)OR¹¹, —CN, —C(O)NR¹³R¹⁴, —NR¹³R¹⁴, —NR¹³C(O)R¹¹, —NR¹³S(O)_(n)R¹²,—NR¹³S(O)_(n)NR¹³R¹⁴, —NR¹³C(O)OR¹², —NR¹³C(O)NR¹³R¹⁴, —NO₂,—S(O)_(n)R¹², —S(O)_(n)NR¹³R¹⁴, heterocycle, heteroaryl, aryl, alkenyl,alkynyl, lower alkyl, lower alkyl substituted with hydroxy, lower alkylsubstituted with lower alkoxy, lower alkyl substituted with —NR¹³R¹⁴,and lower alkyl substituted with heterocycle. For avoidance of doubt,each of said ring systems may be appended to the carbon bearing R² andR³ at any open valence on either of the rings in the ring systems.In some embodiments, R¹ is a ring system selected from

wherein each of said ring systems is optionally substituted with one ormore groups selected from halo, CF₃, —CF₂H, cycloalkyl, —C(O)R¹¹,C(O)OR¹¹, —CN, —C(O)NR¹³R¹⁴, —NR¹³R¹⁴, —NR¹³C(O)R¹¹, —NR¹³S(O)_(n)R¹²,—NR¹³S(O)_(n)N¹³R¹⁴, —NR¹²C(O)OR¹², —NR¹³C(O)NR¹³R¹⁴, —NO₂,—S(O)_(n)R¹², —S(O)_(n)NR¹³R¹⁴, heterocycle, heteroaryl, aryl, alkenyl,alkynyl, lower alkyl, lower alkyl substituted with hydroxy, lower alkylsubstituted with lower alkoxy, lower alkyl substituted with —NR¹³R¹⁴,and lower alkyl substituted with heterocycle. For avoidance of doubt,each of said ring systems depicted above is appended to the carbonbearing R² and R³ at the position indicated.

In some embodiments, R² and R³ are independently selected from hydrogenand C₁-C₆ alkyl or R² and R³, together with the carbon to which they areattached, form a 3-membered cycloalkyl. In some embodiments, R² ishydrogen and R³ is selected from hydrogen and C₁-C₆ alkyl. In someembodiments, R² is hydrogen and R³ is selected from hydrogen and methyl.In some embodiments, R² and R³ are hydrogen. In some embodiments, R² andR³, together with the carbon to which they are attached, form a3-membered cycloalkyl.

In some embodiments, R⁴ is aryl optionally substituted with one or moregroups selected from

-   -   lower alkyl optionally substituted with one or more groups        selected from hydroxy, lower alkoxy, cyano, halo, —C(O)OR¹¹,        —C(O)NR¹³R¹⁴, —NR¹³R¹⁴, —OC(O)R¹¹, —NR¹³C(O)R¹¹,        —NR¹³S(O)_(n)R¹², —NR¹³S(O)_(n)NR¹³R¹⁴, —NR¹³C(O)OR¹², and        —NR¹³C(O)NR¹³R¹⁴,    -   lower alkoxy optionally substituted with one or more groups        selected from halo, hydroxy, and lower alkoxy,    -   heterocycle optionally substituted with one or more groups        selected from lower alkyl, halo, hydroxy, and lower alkoxy,    -   heteroaryloxy optionally substituted with one or more groups        selected from lower alkyl, halo, hydroxy, and lower alkoxy,    -   aryl optionally substituted with one or more groups selected        from lower alkyl, halo, hydroxy, and lower alkoxy,    -   heteroaryl optionally substituted with one or more groups        selected from lower alkyl, halo, hydroxy, and lower alkoxy,    -   halo, cyano, —C(O)R¹¹, —C(O)OR¹¹, —NR¹³R¹⁴, —NR¹³C(O)R¹¹,        —NR¹³S(O)_(n)R¹², —NR¹³S(O)_(n)NR¹³R¹⁴, —NR¹³C(O)OR¹²,        —NR¹³C(O)NR¹³R¹⁴, —C(O)NR¹³R¹⁴, —S(O)_(n)R¹², and        —S(O)_(n)NR¹³R¹⁴.

In some embodiments, R⁴ is aryl optionally substituted with one or moregroups selected from halo, hydroxy, —NR¹³S(O)_(n)R¹², lower alkoxy,lower alkyl, lower alkyl substituted with hydroxy, lower alkylsubstituted with lower alkoxy, lower alkoxy substituted with hydroxy,and lower alkoxy substituted with lower alkoxy.

In some embodiments, R⁴ is phenyl optionally substituted with one ormore groups selected from lower alkoxy, lower alkoxy substituted withhydroxy, and lower alkoxy substituted with lower alkoxy.

In some embodiments, R⁴ is heterocycle optionally substituted with oneor more groups selected from

-   -   lower alkyl optionally substituted with one or more groups        selected from hydroxy, lower alkoxy, cyano, halo, —C(O)OR¹¹,        —C(O)NR¹³R¹⁴, —NR¹³R¹⁴, —OC(O)R¹¹, —NR¹³C(O)R¹¹,        —NR¹³S(O)_(n)R¹², —NR¹³S(O)_(n)NR¹³R¹⁴, —NR¹³C(O)OR¹², and        —NR¹³C(O)NR¹³R¹⁴,    -   lower alkoxy optionally substituted with one or more groups        selected from halo, hydroxy, and lower alkoxy,    -   heterocycle optionally substituted with one or more groups        selected from lower alkyl, halo, hydroxy, and lower alkoxy,    -   halo, cyano, —C(O)R¹¹, —C(O)OR¹¹, —NR¹³R¹⁴, —NR¹³C(O)R¹¹,        —NR¹³S(O)_(n)R¹², —NR¹³S(O)_(n)NR¹³R¹⁴, —NR¹³C(O)OR¹²,        —NR¹³C(O)NR¹³R¹⁴, —C(O)NR¹³R¹⁴, —S(O)_(n)R¹², and        —S(O)_(n)NR¹³R¹⁴.

In some embodiments, R⁴ is selected from pyrrolidin-1-yl,piperidin-1-yl, tetrahydro-2H-pyran-4-yl, morpholin-4-yl, and6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl, each of which is optionallysubstituted with one or more groups selected from

-   -   lower alkyl optionally substituted with one or more groups        selected from hydroxy, lower alkoxy, cyano, halo, —C(O)OR¹¹,        —C(O)NR¹³R¹⁴, —NR¹³R¹⁴, —OC(O)R¹¹, —NR¹³C(O)R¹¹,        —NR¹³S(O)_(n)R¹², —NR¹³S(O)_(n)NR¹³R¹⁴, —NR¹³C(O)OR¹², and        —NR¹³C(O)NR¹³R¹⁴,    -   lower alkoxy optionally substituted with one or more groups        selected from halo, hydroxy, and lower alkoxy,    -   heterocycle optionally substituted with one or more groups        selected from lower alkyl, halo, hydroxy, and lower alkoxy,    -   halo, cyano, —C(O)R¹¹, —C(O)OR¹¹, —NR¹³R¹⁴, —NR¹³C(O)R¹¹,        —NR¹³S(O)_(n)R¹², —NR¹³S(O)_(n)NR¹³R¹⁴, —NR¹³C(O)OR¹²,        —NR¹³C(O)NR¹³R¹⁴, —C(O)NR¹³R¹⁴, —S(O)_(n)R¹², and        —S(O)_(n)NR¹³R¹⁴.

In some embodiments, R⁴ is selected from pyrrolidin-1-yl,piperidin-1-yl, tetrahydro-2H-pyran-4-yl, morpholin-4-yl, and6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl, each of which is optionallysubstituted with one or more groups selected from halo, CF₃, —CF₂H,hydroxy, lower alkyl, lower alkyl substituted with hydroxy, and loweralkyl substituted with lower alkoxy.

In some embodiments, R⁴ is heteroaryl optionally substituted with one ormore groups selected from

-   -   lower alkyl optionally substituted with one or more groups        selected from hydroxy, lower alkoxy, cyano, halo, —C(O)OR¹¹,        —C(O)NR¹³R¹⁴, —NR¹³R¹⁴, —OC(O)R¹¹, —NR¹³C(O)R¹¹,        —NR¹³S(O)_(n)R¹², —NR¹³S(O)_(n)NR¹³R¹⁴, —NR¹³C(O)OR¹², and        —NR¹³C(O)NR¹³R¹⁴,    -   lower alkoxy optionally substituted with one or more groups        selected from halo, hydroxy, and lower alkoxy,    -   heterocycle optionally substituted with one or more groups        selected from lower alkyl, halo, hydroxy, and lower alkoxy,    -   halo, cyano, —C(O)R¹¹, —C(O)OR¹¹, —NR¹³R¹⁴, —NR¹³C(O)R¹¹,        —NR¹³S(O)_(n)R¹², —NR¹³S(O)_(n)NR¹³R¹⁴, —NR¹³C(O)OR¹²,        —NR¹³C(O)NR¹³R¹⁴, —C(O)NR¹³R¹⁴, —S(O)_(n)R¹², and        —S(O)_(n)NR¹³R¹⁴.

In some embodiments, R⁴ is selected from 1H-pyrazol-1-yl,1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-imidazol-1-yl, 1H-imidazol-4-yl,oxazol-2-yl, thiazol-2-yl, isoxazol-3-yl, isoxazol-5-yl, 1H-pyrrol-2-yl,1H-pyrrol-3-yl, thiophen-2-yl, thiophen-3-yl, pyridin-2-yl,pyridin-3-yl, and pyridin-4-yl, each of which is optionally substitutedwith one or more groups selected from

-   -   lower alkyl optionally substituted with one or more groups        selected from hydroxy, lower alkoxy, cyano, halo, —C(O)OR¹¹,        —C(O)NR¹³R¹⁴, —NR¹³R¹⁴, —OC(O)R¹¹, —NR¹³C(O)R¹¹,        —NR¹³S(O)_(n)R¹², —NR¹³S(O)_(n)NR¹³R¹⁴, —NR¹³C(O)OR¹², and        —NR¹³C(O)NR¹³R¹⁴,    -   lower alkoxy optionally substituted with one or more groups        selected from halo, hydroxy, and lower alkoxy,    -   heterocycle optionally substituted with one or more groups        selected from lower alkyl, halo, hydroxy, and lower alkoxy,    -   halo, cyano, —C(O)R¹¹, —C(O)OR¹¹, —NR¹³R¹⁴, —NR¹³C(O)R¹¹,        —NR¹³S(O)_(n)R¹², —NR¹³S(O)_(n)NR¹³R¹⁴, —NR¹³C(O)OR¹²,        —NR¹³C(O)NR¹³R¹⁴, —C(O)NR¹³R¹⁴, —S(O)_(n)R¹², and        —S(O)_(n)NR¹³R¹⁴.

In some embodiments, R⁴ is selected from 1H-pyrazol-1-yl,1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-imidazol-1-yl, 1H-imidazol-4-yl,oxazol-2-yl, thiazol-2-yl, isoxazol-3-yl, isoxazol-5-yl, 1H-pyrrol-2-yl,1H-pyrrol-3-yl, thiophen-2-yl, thiophen-3-yl, pyridin-2-yl,pyridin-3-yl, and pyridin-4-yl, each of which is optionally substitutedwith one or more groups selected from

-   -   lower alkyl optionally substituted with one or more groups        selected from hydroxy, lower alkoxy, cyano, halo, —C(O)OR¹¹,        —C(O)NR¹³R¹⁴, —NR¹³R¹⁴, —OC(O)R¹¹, —NR¹³C(O)R¹¹,        —NR¹³S(O)_(n)R¹², —NR¹³S(O)_(n)NR¹³R¹⁴, —NR¹³C(O)OR¹², and        —NR¹³C(O)NR¹³R¹⁴, and    -   heterocycle optionally substituted with one or more groups        selected from lower alkyl, halo, hydroxy, and lower alkoxy,

In some embodiments, R⁴ is selected from 1H-pyrazol-1-yl,1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-imidazol-1-yl, 1H-imidazol-4-yl,oxazol-2-yl, thiazol-2-yl, isoxazol-3-yl, isoxazol-5-yl, 1H-pyrrol-2-yl,1H-pyrrol-3-yl, thiophen-2-yl, thiophen-3-yl, pyridin-2-yl,pyridin-3-yl, and pyridin-4-yl, each of which is optionally substitutedwith one or more groups selected from lower alkyl optionally substitutedwith one or more groups selected from hydroxy, lower alkoxy, cyano, andhalo.

In some embodiments, R⁴ is lower alkyl.

In some embodiments, R⁵ is hydrogen.

In some embodiments, n is 0. In some embodiments, n is 1. In someembodiments, n is 2.

Also provided is at least one compound selected from compounds 1 to 332and/or at least one pharmaceutically acceptable salt described herein.

The compounds described herein, and/or the pharmaceutically acceptablesalts thereof, can be synthesized from commercially available startingmaterials by methods well known in the art. The following schemesillustrate methods for most of compound preparation. In each of theschemes, LG and LG′ are leaving groups that can be same or different. Y′is —NHR⁷, —OH, —SH, —B(OH)₂, or B(OR′)₂, and R¹, R², R³, R⁴, R⁵ and Yare as defined herein.

The compounds thus obtained can be further modified at their peripheralpositions to provide the desired compounds. Synthetic chemistrytransformations are described, for example, in R. Larock, ComprehensiveOrganic Transformations, VCH Publishers (1989); T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, 3^(rd) Ed., John Wileyand Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagentsfor Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995) and subsequent editions thereof.

Before use, the at least one compound and/or at least onepharmaceutically acceptable salt described herein, can be purified bycolumn chromatography, high performance liquid chromatography,crystallization, or other suitable methods.

Also provided is a composition containing at least one compound and/orat least one pharmaceutically acceptable salt described herein, and atleast one pharmaceutically acceptable carrier.

A composition comprising at least one compound and/or at least onepharmaceutically acceptable salt described herein, can be administeredin various known manners, such as orally, parenterally, by inhalationspray, or via an implanted reservoir. The term “parenteral” as usedherein includes subcutaneous, intracutaneous, intravenous,intramuscular, intraarticular, intraarterial, intrasynovial,intrasternal, intrathecal, intralesional and intracranial injection orinfusion techniques.

An oral composition can be any orally acceptable dosage form including,but not limited to, tablets, capsules, emulsions, and aqueoussuspensions, dispersions and solutions. Commonly used carriers fortablets include lactose and corn starch. Lubricating agents, such asmagnesium stearate, are also typically added to tablets. For oraladministration in a capsule form, useful diluents include lactose anddried corn starch. When aqueous suspensions or emulsions areadministered orally, the active ingredient can be suspended or dissolvedin an oily phase combined with emulsifying or suspending agents. Ifdesired, certain sweetening, flavoring, or coloring agents can be added.

A sterile injectable composition (e.g., aqueous or oleaginoussuspension) can be formulated according to techniques known in the artusing suitable dispersing or wetting agents (such as, for example, Tween80) and suspending agents. The sterile injectable preparation can alsobe a sterile injectable solution or suspension in a non-toxicparenterally acceptable diluent or solvent, for example, as a solutionin 1,3-butanediol. Among the pharmaceutically acceptable vehicles andsolvents that can be employed are mannitol, water, Ringer's solution andisotonic sodium chloride solution. In addition, sterile, fixed oils areconventionally employed as a solvent or suspending medium (e.g.,synthetic mono- or di-glycerides). Fatty acids, such as oleic acid andits glyceride derivatives are useful in the preparation of injectables,as are natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions can also contain a long-chain alcohol diluentor dispersant, or carboxymethyl cellulose or similar dispersing agents.

An inhalation composition can be prepared according to techniques wellknown in the art of pharmaceutical formulation and can be prepared assolutions in saline, employing benzyl alcohol or other suitablepreservatives, absorption promoters to enhance bioavailability,fluorocarbons, and/or other solubilizing or dispersing agents known inthe art.

A topical composition can be formulated in form of oil, cream, lotion,ointment and the like. Suitable carriers for the composition includevegetable or mineral oils, white petrolatum (white soft paraffin),branched chain fats or oils, animal fats and high molecular weightalcohols (greater than C12). In some embodiments, the pharmaceuticallyacceptable carrier is one in which the active ingredient is soluble.Emulsifiers, stabilizers, humectants and antioxidants may also beincluded as well as agents imparting color or fragrance, if desired.Additionally, transdermal penetration enhancers may be employed in thesetopical formulations. Examples of such enhancers can be found in U.S.Pat. Nos. 3,989,816 and 4,444,762.

Creams may be formulated from a mixture of mineral oil, self-emulsifyingbeeswax and water in which mixture the active ingredient, dissolved in asmall amount of an oil, such as almond oil, is admixed. An example ofsuch a cream is one which includes about 40 parts water, about 20 partsbeeswax, about 40 parts mineral oil and about 1 part almond oil.Ointments may be formulated by mixing a solution of the activeingredient in a vegetable oil, such as almond oil, with warm softparaffin and allowing the mixture to cool. An example of such anointment is one which includes about 30% by weight almond and about 70%by weight white soft paraffin.

A pharmaceutically acceptable carrier refers to a carrier that iscompatible with active ingredients of the composition (and in someembodiments, capable of stabilizing the active ingredients) and notdeleterious to the subject to be treated. For example, solubilizingagents, such as cyclodextrins (which form specific, more solublecomplexes with the at least one compound and/or at least onepharmaceutically acceptable salt described herein), can be utilized aspharmaceutical excipients for delivery of the active ingredients.Examples of other carriers include colloidal silicon dioxide, magnesiumstearate, cellulose, sodium lauryl sulfate, and pigments such as D&CYellow #10.

Suitable in vitro assays can be used to preliminarily evaluate theefficacy of the at least one compound and/or at least onepharmaceutically acceptable salt described herein, in inhibiting theactivity of c-Met. The at least one compound and/or at least onepharmaceutically acceptable salt described herein, can further beexamined for efficacy in treating cancer by in vivo assays. For example,the compounds described herein, and/or the pharmaceutically acceptablesalts thereof, can be administered to an animal (e.g., a mouse model)having cancer and its therapeutic effects can be accessed. Based on theresults, an appropriate dosage range and administration route foranimals, such as humans, can also be determined.

Also provided is a method of inhibiting the activity of c-Met. Themethod comprises contacting the receptor with an amount of at least onecompound and/or at least one pharmaceutically acceptable salt describedherein effective to inhibit the activity of c-Met.

The at least one compound and/or at least one pharmaceuticallyacceptable salt described herein can be used to achieve a beneficialtherapeutic or prophylactic effect, for example, in subjects withcancer. As used herein, the term “cancer” refers to a cellular disordercharacterized by uncontrolled or disregulated cell proliferation,decreased cellular differentiation, inappropriate ability to invadesurrounding tissue, and/or ability to establish new growth at ectopicsites. The term “cancer” includes, but is not limited to, solid tumorsand bloodborne tumors. The term “cancer” encompasses diseases of skin,tissues, organs, bone, cartilage, blood, and vessels. The term “cancer”further encompasses primary and metastatic cancers.

Non-limiting examples of solid tumors include pancreatic cancer; bladdercancer; colorectal cancer; breast cancer, including metastatic breastcancer; prostate cancer, including androgen-dependent andandrogen-independent prostate cancer; renal cancer, including, e.g.,metastatic renal cell carcinoma; hepatocellular cancer; lung cancer,including, e.g., non-small cell lung cancer (NSCLC), bronchioloalveolarcarcinoma (BAC), and adenocarcinoma of the lung; ovarian cancer,including, e.g., progressive epithelial or primary peritoneal cancer;cervical cancer; gastric cancer; esophageal cancer; head and neckcancer, including, e.g., squamous cell carcinoma of the head and neck;skin cancer, including e.g., malignant melanoma; neuroendocrine cancer,including metastatic neuroendocrine tumors; brain tumors, including,e.g., glioma, anaplastic oligodendroglioma, adult glioblastomamultiforme, and adult anaplastic astrocytoma; bone cancer; soft tissuesarcoma; and thyroid carcinoma.

Non-limiting examples of hematologic malignancies include acute myeloidleukemia (AML); chronic myelogenous leukemia (CML), includingaccelerated CML and CML blast phase (CML-BP); acute lymphoblasticleukemia (ALL); chronic lymphocytic leukemia (CLL); Hodgkin's disease(HD); non-Hodgkin's lymphoma (NHL), including follicular lymphoma andmantle cell lymphoma; B-cell lymphoma; T-cell lymphoma; multiple myeloma(MM); Waldenstrom's macroglobulinemia; myelodysplastic syndromes (MDS),including refractory anemia (RA), refractory anemia with ringedsiderblasts (RARS), (refractory anemia with excess blasts (RAEB), andRAEB in transformation (RAEB-T); and myeloproliferative syndromes.

In some embodiments, the examples of the cancer to be treated include,but are not limited to, lung cancer, head and neck cancer, colorectalcancer, pancreatic cancer, colon cancer, breast cancer, ovarian cancer,prostate cancer, stomach cancer, kidney cancer, liver cancer, braincancer, bone cancer, and leukemia.

In some embodiments, the at least one compound and/or at least onepharmaceutically acceptable salt described herein, is administered inconjunction with another therapeutic agent. In some embodiments, theother therapeutic agent is one that is normally administered to patientswith the disease or condition being treated. The at least one compoundand/or at least one pharmaceutically acceptable salt described herein,may be administered with the other therapeutic agent in a single dosageform or as a separate dosage form. When administered as a separatedosage form, the other therapeutic agent may be administered prior to,at the same time as, or following administration of the at least onecompound and/or at least one pharmaceutically acceptable salt describedherein.

In some embodiments, at least one compound and/or at least onepharmaceutically acceptable salt described herein, is administered inconjunction with an anti-neoplastic agent. As used herein, the term“anti-neoplastic agent” refers to any agent that is administered to asubject with cancer for purposes of treating the cancer. Nonlimitingexamples anti-neoplastic agents include: radiotherapy; immunotherapy;DNA damaging chemotherapeutic agents; and chemotherapeutic agents thatdisrupt cell replication.

Non-limiting examples of DNA damaging chemotherapeutic agents includetopoisomerase I inhibitors (e.g., irinotecan, topotecan, camptothecinand analogs or metabolites thereof, and doxorubicin); topoisomerase IIinhibitors (e.g., etoposide, teniposide, and daunorubicin); alkylatingagents (e.g., melphalan, chlorambucil, busulfan, thiotepa, ifosfamide,carmustine, lomustine, semustine, streptozocin, decarbazine,methotrexate, mitomycin C, and cyclophosphamide); DNA intercalators(e.g., cisplatin, oxaliplatin, and carboplatin); DNA intercalators andfree radical generators such as bleomycin; and nucleoside mimetics(e.g., 5-fluorouracil, capecitibine, gemcitabine, fludarabine,cytarabine, mercaptopurine, thioguanine, pentostatin, and hydroxyurea).

Chemotherapeutic agents that disrupt cell replication include:paclitaxel, docetaxel, and related analogs; vincristine, vinblastin, andrelated analogs; thalidomide and related analogs (e.g., CC-5013 andCC-4047); protein tyrosine kinase inhibitors (e.g., imatinib mesylateand gefitinib); proteasome inhibitors (e.g., bortezomib); NF-kappa Binhibitors, including inhibitors of I kappa B kinase; antibodies whichbind to proteins overexpressed in cancers and thereby downregulate cellreplication (e.g., trastuzumab, rituximab, cetuximab, and bevacizumab);and other inhibitors of proteins or enzymes known to be upregulated,over-expressed or activated in cancers, the inhibition of whichdownregulates cell replication.

EXAMPLES

The examples below are intended to be purely exemplary and should not beconsidered to be limiting in any way. Efforts have been made to ensureaccuracy with respect to numbers used (for example, amounts,temperature, etc.) but some experimental errors and deviations should beaccounted for. Unless indicated otherwise, parts are parts by weight,temperature is in degrees Centigrade, and pressure is at or nearatmospheric. All MS data were checked by agilent 6120 agilent 1100. Allreagents, except intermediates, used in this invention are commerciallyavailable. All compound names except the reagents were generated byChemdraw 8.0.

In the following examples, the abbreviations below are used:

-   AIBN a,a′-azo-isobutyronnitrile-   BINAP 2,7-Bis(diphenylphosphino)-1,1′-binaphthyl-   Boc tert-butoxycarbonyl-   Boc₂O di-t-butyl-dicarbonate-   i-BuNO₂ Isobutylnitrite-   DCM dichloromethane-   DMF N,N-dimethylformamide-   DMAP 4-Dimethylaminopyridine-   DPPA Diphenylphosphoryl azide-   DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DEA N,N-diethylamine-   ee enantiomeric excess-   Et₃N triethylamine-   h hour-   HATU O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetra-methyluronium    hexafluorophosphate-   HMTA Hexamethylenetetramine-   HOAc acetic acid-   Lawesson's reagent    2,4-Bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane-   mL milliliter(s)-   min minute(s)-   MeOH methanol-   MsCl methanesulfonyl chloride-   NBS N-Bromosuccinimide-   Pd(dppf)Cl₂    1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride    dichloromethane complex-   Pd₂(dba)₃ Tris(dibenzylideneacetone)dipalladium(0)-   Pd(PPh3)₄ Tetrakis(triphenylphosphine)palladium(0)-   PPh₃ Triphenylphosphine-   THF tetrahydrofuran-   Ti(i-OPr)₄ Titanium(IV) isopropoxide-   Xantphos 9-Dimethyl-4,5-bis(diphenylphosphino)xanthene

Synthesis of Amine (NH₂CR¹R²R³ in scheme I and II) Intermediate A

1H-Prrolo[2,3-b]pyridine-3-carbaldehyde (A-2)

To a solution of 1H-pyrrolo[2,3-b]pyridine (A-1) (7.23 g, 61.2 mmol) inacetic acid (20 mL) and water (40 mL) was added HMTA (9.42 g, 67.3mmol). The reaction mixture was stirred at 120° C. for 6 h. It wascooled with an ice bath, and the resulting precipitate was collected anddried to afford the title compound (7.90 g) MS (m/z): 147 (M+1)⁺.

1H-Prrolo[2,3-b]pyridin-3-yl)methanol (A-3

To a solution of 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (A-2) (5.0 g,34.21 mmol) in EtOH (150 mL) was added NaBH₄ (1.30 g, 34.21 mmol). Thereaction mixture was stirred at room temperature for 0.5 h. It wasconcentrated and purified by chromatography on silica gel to afford thetitle compound (5.0 g). MS (m/z): 149 (M+1)⁺.

3-(Aidomethyl)-1H-pyrrolo[2,3-b]pyridine (A-4)

To a mixture of 1H-pyrrolo[2,3-b]pyridin-3-yl)methanol (A-3) (1.0 g,6.75 mmol) in anhydrous THF (50 mL) were added DPPA (3.71 g, 13.5 mmol)and DBU (0.821 g, 5.4 mmol) respectively. It was refluxed under N₂ for 6h, and then concentrated under vacuo. The resulting residue wasdissolved in EtOAc (50 mL), washed with brine, dried over sodium sulfateand concentrated under vacuo, to obtain the crude product. The crudeproduct was purified by chromatography on silica gel to afford the titlecompound (0.587 g). MS (m/z): 174 (M+1)⁺.

1H-Prrolo[2,3-b]pyridin-3-yl)methanamine (A

To a mixture of 3-(azidomethyl)-1H-pyrrolo[2,3-b]pyridine (A-4) (1.50 g,8.63 mmol) in EtOAc (150 mL) was added 10% Pd/C (1.10 g). The resultingreaction mixture was stirred under one atmosphere of H₂ at roomtemperature for 3 h. The mixture was filtered, and the filtrate wasconcentrated to afford the title compound (1.15 g).

Intermediate B

1-(2-Cloropyridin-3-yl)ethanone (B-2)

To a solution of 2-chloronicotinic acid (B-1) (7.88 g, 50.0 mmol) in THF(100 mL) was added methyl magnesium bromide (42 mL, 3-Methyl ethersolution) dropwise under 0° C. Upon completion of the addition, thereaction mixture was stirred at 0° C. for 0.5 h and then at roomtemperature overnight. The reaction mixture was added into ice/water(150 mL), and extracted with ethyl acetate. The combined organic layerswere dried over Na₂SO₄ and concentrated to afford the title compound1-(2-chloropyridin-3-yl)ethanone (B-2). MS (m/z): 156 (M+1)⁺.

3-Methyl-1H-pyrazolopyrrolo[3,4-b]pyridine (B-3)

A solution of 1-(2-chloropyridin-3-yl)ethanone (B-2) (6 g, 38.6 mmol)and hydrazine (85%, 9.1 g, 154.4 mmol) in pyridine (80 mL) was stirredunder reflux overnight. The mixture was cooled to room temperature,concentrated, diluted with water (80 mL) and then extracted with ethylacetate (100 mL×3). The combined organic layers were washed with brine,dried over Na₂SO₄, and concentrated under vacuo. The resulting residuewas used for the next step without further purification. MS (m/z): 134(M+1)⁺.

tert-Butyl 3-methyl-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (B-4)

To a solution of 3-methyl-1H-pyrazolo[3,4-b]pyridine (B-3) in EtOAc (300mL) were added (Boc)₂O (16.4 g, 75 mmol), DMAP (610 mg, 5 mmol), andEt₃N (10 g, 100 mmol). The reaction mixture was stirred at roomtemperature overnight. Solvent was removed in vacuo, and the residue waspurified by chromatography on silica gel to afford the title compound(5.3 g, 45.5% by two steps). MS (m/z): 134.

3-(Bromomethyl)-1H-pyrazolo[3,4-b]pyridine (B-5)

To a solution of tert-butyl3-methyl-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (B-4) (699 mg, 3 mmol)in CCl₄ (15 mL) were added NBS (641 mg, 3.6 mmol) and AIBN (70 mg, 0.3mmol). The reaction mixture was stirred under reflux overnight and thenfiltered. The filtrate was washed with saturated aqueous Na₂CO₃ (15 mL).The organic layer was dried over Na₂SO₄ and concentrated to afford thecrude product. The crude product was used for next step without furtherpurification. MS (m/z): 212 (M+1)⁺.

3-(Amidomethyl)-1H-pyrazolo[3,4-b]pyridine (B-6)

A mixture of 3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridine (B-5) and NaN₃(390 mg, 6 mmol) in DMF (6 mL) was stirred at 80° C. for 1.5 h. Afterthe mixture was cooled to room temperature, water (25 mL) was added. Theresulting mixture was extracted with ethyl acetate (40 mL×3). Thecombined organic layers were washed with brine (40 mL) and dried overNa₂SO₄. Solvent was removed in vacuo, and the residue was purified bychromatography on silica gel. A solid was obtained (152 mg, 29.1% by twosteps).

1H-Pzolo[3,4-b]pyridin-3-yl)methanaminium chloride (B

A mixture of 3-(azidomethyl)-1H-pyrazolo[3,4-b]pyridine (B-6) (152 mg,0.87 mmol), PPh₃ (465 mg, 1.74 mmol) and 1 mL of NH₄OH in THF (20 mL)was stirred at room temperature overnight. The solution wasconcentrated, and the resulting residue was dissolved in ethyl acetate.The solution was treated with 2M HCl, which resulted in precipitates.The precipitates were collected by filtration to afford the titlecompound (121 mg). MS (m/z): 149 (M+1)⁺.

Intermediate C

Methyl 3-aminothieno[3,2-b]pyridine-2-carboxylate (C-2)

To a mixture of 3-chloropyridine-2-carbonitrile (C-1) (1.01 g, 7.29mmol) and K₂CO₃ (1.10 g, 7.96 mmol) in DMF (10 mL) and water (1 mL) wasadded methyl thioglycolate (0.709 mL, 7.93 mmol) dropwise. The reactionmixture was stirred at 40° C. for 3 h. The mixture was quenched withcold water (70 mL) and placed on ice to enhance precipitation. Theprecipitate was collected by filtration to afford the title compound. MS(m/z): 209 (M+1)⁺.

Methyl thieno[3,2-b]pyridine-2-carboxylate (C-3)

To a solution of methyl 3-aminothieno[3,2-b]pyridine-2-carboxylate (C-2)(930 mg, 4.47 mmol) in hypophosphorous acid (35 mL) chilled in an icebath was added sodium nitrite (620 mg, 8.98 mmol) in a minimal amount ofwater. The reaction mixture was stirred for 3 h in an ice bath, and thenthe pH was adjusted to about 7.0 with 30% aqueous sodium hydroxidesolution. The resulting mixture was extracted with EtOAc. The combinedorganic layers were dried and concentrated to afford the title compound.MS (m/z): 194 (M+1)⁺.

Thieno[3,2-b]pyridin-2-ylmethanol (C-4)

To a solution of methyl thieno[3,2-b]pyridine-2-carboxylate (C-3) (600mg, 3.1 mmol) in 30 mL of anhydrous THF at 0° C. was added LiAlH₄ (472mg, 12.4 mmol) in anhydrous THF (25 mL) dropwise over 20 mins. Thereaction mixture was stirred at 0° C. for 30 mins. MeOH was added andthe resulting mixture was purified by chromatography to afford the titlecompound. MS (m/z): 166 (M+1)⁺.

2-(Chloromethyl)thieno[3,2-b]pyridine (C-5)

To a solution of thieno[3,2-b]pyridin-2-ylmethanol (C-4) (17 mg, 0.1mmol) in anhydrous dichloromethane (10 mL) was added SOCl₂ (120 mg).After the mixture was stirred at room temperature for 2 hours, it wasconcentrated and used for the next step without further purification. MS(m/z): 184 (M+1)⁺.

Thieno[3,2-b]pyridin-2-ylmethanamine (C)

2-(Chloromethyl)thieno[3,2-b]pyridine (C-5) (183 mg, 1 mmol) wasdissolved in NH₃/methanol (7 N, 10 mL). The resulting mixture wasstirred at 50° C. for 16 hours and concentrated. The residue waspurified by chromatography. MS (m/z): 165 (M+1)⁺.

Intermediates D and D′ Methyl thieno[3,2-c]pyridine-2-carboxylate (D-2)

To a solution of 4-chloropyridine-3-carboxaldehyde (D-1) (1.4 g, 10mmol) dissolved in DMF (10 mL) and water (1 mL) were added K₂CO₃ (1.66g, 12 mmol) and methyl thioglycolate (1.07 mL, 12 mmol) portion-wise.The reaction mixture was stirred at 45° C. overnight and then quenchedwith cold water. The flask was placed on ice to enhance precipitation.The precipitate was collected by filtration and air-dried to afford thetitle compound (1.23 g). MS (m/z): 194 (M+1)⁺.

Thieno[3,2-c]pyridin-2-ylmethanol (D-3)

To a solution of methyl thieno[3,2-c]pyridine-2-carboxylate (D-2) (15 g,77.6 mmol) in anhydrous THF (250 mL) was added LiAlH₄ (4.42 g, 116.4mmol) in portions at 0° C. The suspension was stirred at 0° C. for 1 hand then quenched by adding saturated aqueous NH₄Cl and filtered. Thefiltrate was washed with brine and concentrated. The residue was used inthe next step without any further purification (10.3 g).

2-(Azidomethyl)thieno[3,2-c]pyridine (D-4)

To a flame-dried round-bottomed flask containingthieno[3,2-c]pyridin-2-ylmethanol (D-3) (3.2 g, 19.4 mmol) was addedDPPA (8 g, 6.26 mL, 29.1 mmol) in THF (50 mL). The reaction mixture wasstirred for 5 mins and cooled to 0° C., followed by adding DBU (4.43 g,4 mL, 29.1 mmol) via syringe. The mixture was allowed to stir at refluxovernight. The reaction was then partitioned between water and ethylether. The aqueous layer was extracted with ethyl ether. The combinedorganic layers were washed with brine, dried over Na₂SO₄, concentrated,and purified by chromatography to afford the product (3.27 g). MS (m/z):191 (M+1)⁺.

Thieno[3,2-c]pyridin-2-ylmethanamine hydrochloride (D)

To a solution of 2-(azidomethyl)thieno[3,2-c]pyridine (D-4) (3 g, 15.8mmol) in anhydrous THF (50 mL) was added Ph₃P (8.27 g, 31.5 mmol),followed by NH₄OH (2 mL). The solution was stirred at room temperatureovernight. Solvent was removed, and the residue was purified bychromatography to afford the title compound (2.5 g).

Thieno[3,2-c]pyridine-2-carboxylic acid (D′-1)

To a solution of methyl thieno[3,2-c]pyridine-2-carboxylate (D-2) (12 g,62.1 mmol) in MeOH (150 mL) and H₂O (15 mL) was added LiOH.H₂O (5.2 g,124.2 mmol). The solution was stirred at room temperature overnight, andthen acidified with 1N aqueous HCl. The resulting white precipitate wascollected by filtration and air-dried to afford the title compound. MS(m/z): 179 (M)⁺.

N-Methoxy-N-methylthieno[3,2-c]pyridine-2-carboxamide (D′-2)

To a solution of thieno[3,2-c]pyridine-2-carboxylic acid (D′-1) (11.5 g,64.2 mmol) in DCM (200 mL) and DMF (50 mL) was added Et₃N (19.5 g, 26.6mL, 192.6 mmol) followed by HATU (36.6 g, 96.3 mmol). The reactionsolution was stirred at room temperature for 20 mins, and then treatedwith N,O-dimethylhydroxylamine hydrochloride (6.9 g, 70.6 mmol).Stirring continued overnight at room temperature. The solvent wasremoved. The residue was dissolved in EtOAc and washed with water andbrine. The organic layer was dried and concentrated. The residue waspurified by chromatography on silica gel to give the title compound. MS(m/z): 223 (M+1)⁺.

1-(Thieno[3,2-c]pyridin-2-yl)ethanone (D′-3)

To a solution of N-methoxy-N-methylthieno[3,2-c]pyridine-2-carboxamide(D′-2) (11.1 g, 50 mmol) in anhydrous THF (150 mL) was added MeMgBr (3Min ethyl ether, 25 mL, 75 mmol) at 0° C. under N₂. The reaction mixturewas allowed to warm to the ambient temperature and stirred overnight.Saturated aqueous NH₄Cl solution was added to quench the reaction. Theresulting mixture was then extracted with EtOAc. The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated to afford thetitle compound. MS (m/z): 178 (M+1)⁺.

1-(Thieno[3,2-c]pyridin-2-yl)ethanol (D′-4)

To a solution of 1-(thieno[3,2-c]pyridin-2-yl) ethanone (D′-3) (3.5 g, 1mmol) in anhydrous THF (50 mL) was added LiAlH₄ (1.13 g, 1.5 mmol) inportions at 0° C. The suspension was stirred under this temperature for1 h. The reaction mixture was quenched with saturated aqueous NH₄Clsolution and filtered. The filtrate was washed with brine, concentrated,and then used for the next step without any further purification.

1-(Thieno[3,2-c]pyridin-2-yl)ethanamine (D′)

Intermediate D′ was prepared from 1-(thieno[3,2-c]pyridin-2-yl)ethanol(D′-4) following similar procedures for synthesizing intermediate A fromA-3, as described above.

Intermediate E

Thieno[2,3-b]pyridin-2-ylmethanol (E-2)

E-2 was prepared from thieno[2,3-b]pyridine-2-carbaldehyde (E-1)following similar procedures for synthesizing intermediate A-3 from A-2,as described above. MS (m/z): 166 (M+1)⁺.

Thieno[2,3-b]pyridin-2-ylmethanamine (E)

Intermediate E was prepared from thieno[2,3-b]pyridine-2-ylmethanol(E-2) following similar procedures for synthesizing intermediate C fromC-4, as described above. MS (m/z): 165 (M+1)⁺.

Intermediate F

Methyl 5-methylthiophene-2-carboxylate (F-2)

To a solution of 5-methylthiophene-2-carboxylic acid (F-1) (14.0 g, 0.1mol) in MeOH (250 mL) was added concentrated H₂SO₄ (2.0 mL). Thereaction mixture was stirred under reflux for 60 h. The solvent wasremoved in vacuo. Ethyl acetate was added to dilute the reactionmixture. Then the organic solution was washed with a saturated aqueousNa₂CO₃ solution, and dried over Na₂SO₄. The solvent was removed toafford the title compound (13.4 g).

Methyl 5-methyl-4-nitrothiophene-2-carboxylate (F-3)

A solution of concentrated HNO₃ (7.2 mL, 111.5 mmol) in concentratedH₂SO₄ (20 mL) was added dropwise to the solution of methyl5-methylthiophene-2-carboxylate (F-2) (13.4 g, 86.0 mmol) inconcentrated H₂SO₄ (30 mL) at 0° C. The reaction mixture was stirred at0° C. for 30 mins and poured into ice-water. The precipitate wasfiltered and washed with water. A solid was collected as the product(14.8 g).

Methyl 4-amino-5-methylthiophene-2-carboxylate (F-4)

To a solution of methyl 5-methyl-4-nitrothiophene-2-carboxylate (F-3)(14.8 g, 73.6 mmol) in MeOH/THF (1:1, 300 mL) was added Raney Ni. Thereaction mixture was degassed and charged with hydrogen 3 times, andthen stirred at room temperature for 36 h under 1 atmosphere ofhydrogen. Raney Ni was filtered, and the filtrate was concentrated. Theresidue was treated with aqueous HCl (1 N, 150 mL) and filtered. Thefiltrate was treated with aqueous NaOH (1 N) to bring pH to about 8 to9. Then the mixture was extracted with ethyl acetate. The combinedorganic layers were dried over Na₂SO₄, and the solvent was removed togive the title compound (8.1 g).

Methyl 1-acetyl-1H-thieno[3,2-c]pyrazole-5-carboxylate (F-5)

To a solution of methyl 4-amino-5-methylthiophene-2-carboxylate (F-4)(5.1 g, 30 mmol) in toluene (120 mL) were added acetic anhydride (16.0g, 0.12 mol) and potassium acetate (1.5 g, 15.1 mmol). The reactionmixture was stirred at 100° C. for 3 h. After cooled to roomtemperature, the reaction mixture was treated with isobutyl nitrite(10.5 g, 90.0 mmol), and then stirred at 100° C. overnight. Water wasadded, and then the mixture was extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over Na₂SO₄ andconcentrated. The residue was purified by chromatography eluting withPet/EtOAc=10/1 to afford the title compound (5.3 g) as the product.

1H-Thieno[3,2-c]pyrazol-5-yl)methanol (F-6

To a solution of methyl 1-acetyl-1H-thieno[3,2-c]pyrazole-5-carboxylate(F-5) (4.5 g, 20.0 mmol) in MeOH (30 mL) was slowly added NaBH₄ (836 mg,22.0 mmol). The mixture was stirred at room temperature for 30 mins, andthen concentrated. The residue was dissolved in anhydrous THF (80 mL)and then LiAlH₄ (1.5 g, 40.0 mmol) was slowly added at 0° C. Thereaction mixture was stirred at 0° C. for 30 min. Aqueous NH₄Cl solutionwas added dropwise to quench the reaction. The resulting mixture wasfiltered, and the filtrate was extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over Na₂SO₄, andconcentrated in vacuo to give the title compound (2.9 g).

1H-Thieno[3,2-c]pyrazol-5-yl)methanaminium chloride (F

Intermediate F was prepared from (1H-thieno[3,2-c]pyrazol-5-yl)methanol(F-6) following similar procedures for synthesizing intermediate D fromD-3, as described above.

Intermediate G and G′ 1H-Thieno[3,2-c]pyrazole-5-carboxylic acid (G-1)

To a solution of methyl 1-acetyl-1H-thieno[3,2-c]pyrazole-5-carboxylate(F-5) (4.9 g, 21.8 mmol) in MeOH (15 mL) was added an aqueous KOHsolution (6 N, 10 mL). The reaction mixture was stirred at roomtemperature for 2 h, and then concentrated in vacuo. Aqueous HCl (6 N)was added to adjust pH to 5-6. The precipitates were collected byfiltration to afford the title compound (3.0 g).

Methyl 1H-thieno[3,2-c]pyrazole-5-carboxylate (G-2)

To a solution of 1H-thieno[3,2-c]pyrazole-5-carboxylic acid (G-1) (3.0g, 17.9 mmol) in MeOH (50 mL) was added concentrated H₂SO₄ (0.3 mL). Thereaction mixture was stirred at reflux for 60 h. Solvent was removed invacuo. Ethyl acetate was added to dilute the mixture. The mixture waswashed with aqueous NaHCO₃ solution, dried over Na₂SO₄, and concentratedin vacuo to afford the title compound (2.4 g).

Methyl 2-ethyl-2H-thieno[3,2-c]pyrazole-5-carboxylate (G-3) and Methyl1-ethyl-1H-thieno[3,2-c]pyrazole-5-carboxylate (G′-3)

To a solution of methyl 1H-thieno[3,2-c]pyrazole-5-carboxylate (G-2)(760 mg, 4.2 mmol) in DMF (4 mL) were added bromoethane (915 mg, 8.3mmol) and K₂CO₃ (1.7 g, 12.6 mmol). The reaction mixture was stirred at110° C. for 3 h in a sealed tube. After cooled to room temperature, themixture was concentrated and purified by chromatography to afford twoproducts:

Methyl 2-ethyl-2H-thieno[3,2-c]pyrazole-5-carboxylate (351 mg) (G-3). MS(m/z): 211 (M+1)⁺.

Methyl 1-ethyl-1H-thieno[3,2-c]pyrazole-5-carboxylate (272 mg) (G′-3).MS (m/z): 211 (M+1)⁺.

2-Ethyl-2H-thieno[3,2-c]pyrazol-5-yl)methanaminium chloride (G

Intermediate G was prepared from methyl2-ethyl-2H-thieno[3,2-c]pyrazole-5-carboxylate (G-3) following similarprocedures for synthesizing intermediate D from D-2, as described above.MS (m/z): 182 (M+1)⁺.

1-Ethyl-1H-thieno[3,2-c]pyrazol-5-yl)methanamine chloride (G′

Intermediate G′ was prepared from methyl1-ethyl-1H-thieno[3,2-c]pyrazole-5-carboxylate (G′-3) following similarprocedures for synthesizing intermediate D from D-2, as described above.MS (m/z): 182 (M11)⁺.

Intermediate H and H′

1H-Pyrrolo[2,3-b]pyridine-2-carboxamide (H-2)

To a solution of methyl 1H-pyrrolo[2,3-b]pyridine-2-carboxylate (H-1)(880 mg, 5.0 mmol) in MeOH (2 mL) was added NH₃.H₂O (6 mL). The reactionwas heated at 80° C. overnight. After being cooled to room temperature,the mixture was concentrated in vacuo to afford the title compound (805mg) as a yellow solid, which was used for the next step without furtherpurification. MS (m/z): 162 (M+1)⁺.

1H-Pyrrolo[2,3-b]pyridin-2-yl)methanamine (H

To a solution of 1H-pyrrolo[2,3-b]pyridine-2-carboxamide (H-2) (805 mg,5.0 mmol) in dried THF (10 mL) at 0° C. under 1 atm of N₂ was slowlyadded LiAlH₄ (570 mg, 15 mmol). The mixture was stirred at 80° C.overnight. The mixture was then cooled to 0° C. concentrated, and thenpurified by chromatography on silica gel to afford the title compound(720 mg). MS (m/z): 148 (M+1)⁺.

Methyl1-((2-(trimethylsilyl)ethoxy)methyl)-¹H-pyrrolo[2,3-b]pyridine-2-carboxylate(H′-1)

To a solution of methyl 1H-pyrrolo[2,3-b]pyridine-2-carboxylate (H-1)(528 mg, 3 mmol) in dried THF (5 mL) at 0° C. was added NaH (240 mg, 6mmol). The reaction was stirred for 0.5 h under N₂, and then SEMCl (526mg, 3 mmol) was added dropwise. The mixture was stirred at roomtemperature for 2 h. H₂O was added to quench the reaction. The resultingmixture was extracted with EtOAc. The oragnic layer was dried overNa₂SO₄, and concentrated to afford the title compound (750 mg), whichwas used for the next step without purification. MS (m/z): 307 (M+1)⁺.

1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methanamine(H′

Intermediate H′ was prepared from methyl1-((2-(trimethylsilyl)ethoxy)methyl)-¹H-pyrrolo[2,3-b]pyridine-2-carboxylate(H′-1) following similar procedures for synthesizing intermediate D fromD-2, as described above. MS (m/z): 278 (M+1)⁺.

Intermediate I

1H-Pyrrolo[3,2-b]pyridin-2-yl)methanamine (I

Intermediate I was prepared from methyl1H-pyrrolo[3,2-b]pyridine-2-carboxylate (I-1) following similarprocedures for synthesizing intermediate H, as described above. MS(m/z): 148 (M+1)⁺.

Intermediate J

Thieno[2,3-b]pyridine (J-2)

To a vigorously stirred mixture of 2-nitrothiophene (J-1) (13 g, 0.1mol) and concentrated hydrochloric acid (195 mL) was added tin (25 g) at0° C. After most of the tin was dissolved, EtOH (70 mL) and anhydrousZnCl₂ (6 g) were added. The mixture was heated to 85° C., and thentreated with malonaldehyde bis(diethyl acetal) (17.2 g, 0.078 mol) inEtOH (30 mL). The resulting reaction was maintained at 85° C. for 1 h,then poured onto ice (100 g), basified with NH₃.H₂O, and extracted withDCM (75 mL×3). The combined organic layers were concentrated andpurified by chromatography on silica gel to give the title compound. MS(m/z): 135 (M)⁺.

3-Bromothieno[2,3-b]pyridine (J-3)

Bromine (2.08 g, 13 mmol) was dropwise added to a mixture ofthieno[2,3-b]pyridine (J-2) (1.35 g, 10 mmol), dipotassium monohydrogenorthophosphate (940 mg, 5.4 mmol), sodium bicarbonate (840 mg 10 mmol),and magnesium sulfate (2.0 g, 16.7 mmol) in chloroform (40 mL) which hasbeen stirred at reflux for 16 h, the resulting mixture was stirred underreflux for 24 h, then filtered and washed with DCM. The filtrate wasconcentrated, and purified by chromatography. MS (m/z): 214 (M+H)⁺.

Thieno[2,3-b]pyridine-3-carbonitrile (J-4)

To a stirred solution of 3-bromothieno[2,3-b]pyridine (J-3) (107 mg, 0.5mmol) and CuCN (60 mg, 0.67 mmol) in anhydrous DMF (4 mL) was addedPd(PPh₃)₄ (57 mg, 0.05 mmol). The reaction was degassed with nitrogenand stirred at 120° C. for 5 h. Then the cooled mixture was concentratedand purified by chromatography to afford the title compound. MS (m/z):161 (M+1)⁺.

Thieno[2,3-b]pyridin-3-ylmethanamine (J)

To a solution of thieno[2,3-b]pyridine-3-carbonitrile (J-4) (320 mg, 2mmol) in NH₃.EtOH (25 mL) was added Ranye/Ni (about 300 mg). Thereaction was degassed with hydrogen and stirred at room temperature for2 h. Then the mixture was filtered, and the filtrate was concentrated togive the title compound, which was used for next step withoutpurification. MS (m/z): 165 (M+1)⁺.

Intermediate K

H-Imidazo[1,2-a]pyridine-6-carbonitrile (K-2)

To a solution of 6-aminonicotinonitrile (K-1) (4.0 g, 33.6 mmol) inanhydrous EtOH (160 mL) was added 2-chloroacetaldehyde (40% in H₂O, 27.5mL, 168 mmol). The reaction was refluxed for 4 h, and then concentrated.The resulting residue was dissolved in water and adjusted to pH>7 with asaturated NaHCO₃ solution. The precipitate was collected and dried toafford the title compound (4.80 g).

H-Imidazo[1,2-a]pyridin-6-yl)methanamine (K

Intermediate K was prepared from H-imidazo[1,2-a]pyridine-6-carbonitrile(K-2) following similar procedures for synthesizing intermediate J fromJ-4, as described above.

Intermediate L

[1,2,4]triazolo[1,5-a]pyridine-6-carbonitrile (L-2)

To a stirred solution of 6-aminonicotinonitrile (L-1) (8.7 g, 73 mmol)in DMF (35 mL) was added N,N-dimethylformamide dimethyl acetal (35 mL,294 mmol). The reaction mixture was heated to 130° C. overnight. Aftercooled to room temperature, the volatiles were removed under reducedpressure to afford the desired intermediateN′-(5-cyanopyridin-2-yl)-N,N-dimethylformamidine.

To an ice-cooled, stirred solution of the above product in methanol (200mL) and pyridine (11.5 mL, 143 mmol) was added hydroxylamine-O-sulfonicacid (11.3 g, 100 mmol). The reaction mixture was allowed to warm toroom temperature and was stirred overnight. Then the volatiles wereremoved under reduced pressure, and the residue was partitioned betweenaqueous sodium bicarbonate solution and ethyl acetate. The aqueous layerwas further extracted with ethyl acetate. The combined organic layerswere washed sequentially with water and brine, dried over anhydrousNa₂SO₄, filtered, and concentrated. The resulting residue was purifiedby chromatography on silica gel to give the title compound (5.5 g). MS(m/z): 145 (M+1)⁺.

[1,2,4]Triazolo[1,5-a]pyridin-6-ylmethanamine (L)

Intermediate L was prepared from[1,2,4]triazolo[1,5-a]pyridine-6-carbonitrile (L-2) following similarprocedures for synthesizing intermediate J from J-4, as described above.

Inermediate M

Pyrazolo[1,5-a]pyrimidin-5-ylmethanamine (M)

Intermediate M was prepared frompyrazolo[1,5-a]pyrimidine-5-carbonitrile (M−1) following similarprocedures for synthesizing intermediate J from J-4, as described above.MS (m/z): 149 (M+1)⁺.

Intermediate N

Intermediate N was prepared from quinoline-6-carboxylic acid asdescribed in US2007/0265272.

Intermediate O

Quinoline-6-carbonyl chloride (O-2)

To a mixture of quinoline-6-carboxylic acid (0-1) (2.0 g, 11.5 mmol) inCH₂Cl₂ (250 mL) was added 3 drops of DMF at 0° C., followed by oxalylchloride (7.3 g, 57.5 mmol) dropwise. The resulting reaction was stirredat room temperature overnight, and then concentrated to afford the titlecompound (2.2 g).

Quinoline-6-carboxamide (O-3)

To a solution of quinoline-6-carbonyl chloride (0-2) (2.2 g, 10.5 mmol)in THF (100 mL) was added ammonia (5 mL) at 0° C. The mixture wasstirred at room temperature for 1 h, then concentrated and washed withwater (15 mL) to afford the title compound (1.5 g). MS (m/z): 173(M+1)⁺.

Quinoline-6-carbonitrile (O-4)

To a mixture of quinoline-6-carboxamide (0-3) (1.2 g, 7.2 mmol) andtriethylamine (2.2 g, 21.8 mmol) in DCM (50 mL) at 0° C. was addedtrifluoroacetic acid anhydride (1.9 g, 8.9 mmol). The reaction wasstirred for 10 mins at 0° C., then quenched with water. The resultingmixture was extracted with DCM. The organic layer was dried overanhydrous Na₂SO₄, and concentrated to afford the desired title compound(1.0 g). MS (m/z): 154 (M)⁺.

1-(Quinolin-6-yl)cyclopropanamine (O)

Ethylmagnesium bromide (7.7 mmol, 3 M in ethyl ether) was added to asolution of quinoline-6-carbonitrile (0-4) (540 mg, 3.5 mmol) andTi(Oi-Pr)₄ (3.9 mmol, 1.16 mL) in Et₂O (15 mL) at −70° C. The resultingyellow solution was stirred for 10 mins, warmed to room temperature over1.5 h, and then was treated with BF₃.OEt₂ (7 mmol, 0.88 mL). Theresulting mixture was stirred for 1 h. Then 1N aqueous HCl (11 mL) andethyl ether (40 mL) were added, followed by NaOH (10% aq, 30 mL). Themixture was extracted with ethyl ether. The combined ethyl ether layerswere dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo toafford the crude title compound, which was used for the next stepwithout further purification. MS (m/z): 185 (M+1)⁺.

Intermediate P

6-Bromo-7-fluoroquinoline and 6-bromo-5-fluoroquinoline (P-2)

A mixture of 4-bromo-3-fluoroaniline (P-1) (5.7 g, 30 mmol),propane-1,2,3-triol (11.04 g, 120 mmol), FeSO₄.7H₂O (1.92 g, 6.9 mmol),and nitrobenzene (2.22 g, 18 mmol) was stirred at room temperature for10 mins, then concentrated H₂SO₄ (9.7 g, 9.9 mmol) was added. Theresulting mixture was stirred at reflux for 7 h. After cooling to roomtemperature, the reaction was poured into water, basified with NH₃.H₂Oto pH about 8, and extracted with DCM. The concentrated organic layerwas purified by chromatography on silica gel (eluted withPet/EtOAc=15/1) to afford the title compound mixture. 6.78 g. MS (m/z):226 (M+1)⁺

7-Fluoroquinolin-6-yl)methanamine and (5-fluoroquinolin-6-yl)methanamine(P

These compounds were prepared from 6-bromo-7-fluoroquinoline and6-bromo-5-fluoroquinoline (P-2) following similar procedures forsynthesizing Intermediate J from J-3, as described above. MS (m/z): 177(M+1)⁺.

Intermediate Q

5-Chlorothiazolo[5,4-b]pyridin-2-amine (Q-2)

To glacial acetic acid (125 mL) pre-cooled to 5° C. were added potassiumthiocyanate (93 g, 961 mmol) and 6-chloropyridin-3-amine (Q-1) (15 g,117 mmol). The mixture was placed in a freezing mixture of ice and saltand stirred, while 10 mL of bromine in glacial acetic acid (30 mL) wasadded from an addition funnel at such a rate that the temperature neverrose beyond 0° C. After all the bromine had been added, the solution wasstirred for an additional 2 h at 0° C. and at room temperatureovernight. Water (60 mL) was added quickly, and the slurry maintained at90° C. was filtered hot. The orange filter cake was placed in thereaction flask. Glacial acetic acid (60 mL) was added to the flask. Themixture in the flask was maintained at 85° C. was filtered hot onceagain. The combined filtrates were cooled and neutralized withconcentrated ammonia solution to pH 6. A precipitate was collected asthe title compound (19 g). MS (m/z): 186 (M+1)⁺.

3-Amino-6-chloropyridine-2-thiol (Q-3)

5-Chlorothiazolo[5,4-b]pyridin-2-amine (Q-2) (19 g, 103 mmol) containingsodium sulfite (2 g) was refluxed in 20% aqueous sodium hydroxidesolution (150 mL) overnight. The solids were completely dissolved after1 h, then cooled to room temperature. The solution was neutralized withformic acid. A precipitate was collected by filtration as the titlecompound (16.4 g).

5-Chlorothiazolo[5,4-b]pyridine (Q-4)

3-Amino-6-chloropyridine-2-thiol (Q-3) (16.4 g, 103 mmol) in formic acid(80 mL) was refluxed at 110° C. for 2 h. The reaction mixture was cooledand neutralized with concentrated ammonia to pH 7. A precipitate wascollected by filtration as the title compound (14.5 g). MS (m/z): 171(M+1)⁺.

Thiazolo[5,4-b]pyridine-5-carbonitrile (Q-5)

To an 8 mL screw cap vial equipped with a magnetic stirring bar wereadded 5-chlorothiazolo[5,4-b]pyridine (Q-4) (460 mg, 2.7 mmol),Zn(CN)₂(316 mg, 2.7 mmol), Pd₂(dba)₃ (123 mg, 0.13 mmol), DPPF (150 mg,0.27 mmol) and DMF (5 mL, wet, containing 1% of H₂O). The vial wasflushed with nitrogen, then sealed with the screw cap. The mixture wasstirred at 120° C. for overnight, and then concentrated in vacuo. Theresulting residue was purified by chromatography on silica gel to givethe title compound (151 mg).

Thiazolo[5,4-b]pyridin-5-ylmethanamine (Q)

Intermediate Q was prepared from thiazolo[5,4-b]pyridine-5-carbonitrile(Q-5) following similar procedures for synthesizing intermediate J fromJ-4, as described above. MS (m/z): 166 (M+1)⁺.

Intermediate R

Ethyl 2-(4-chloropyridin-3-ylamino)-2-oxoacetate (R-2)

To a solution of 4-chloropyridin-3-amine (R-1) (5 g, 38.9 mmol) in THF(100 mL) was added Et₃N (4.72 g, 6.5 mL, 46.7 mmol), followed by ethyl2-chloro-2-oxoacetate (5.84 g, 4.78 mL, 42.8 mmol) in THF (5 mL)dropwise at 0° C. The resulting mixture was stirred at room temperaturefor 1 h, and then concentrated in vacuo. The resulting residue wasdissolved in EtOAc, and washed with aqueous saturated NaHCO₃. Theorganic layer was separated, dried over Na₂SO₄, and concentrated to givethe title compound, which was used for the next step without furtherpurification. MS (m/z): 229 (M+1)⁺.

Ethyl thiazolo[4,5-c]pyridine-2-carboxylate (R-3)

A solution of ethyl 2-(4-chloropyridin-3-ylamino)-2-oxoacetate (R-2) (8g, 35 mmol) and Lawesson's reagent (8.5 g, 21 mmol) in toluene (100 mL)was refluxed for 2 h, and then concentrated in vacuo. The residue waspurified by chromatography on silica gel to give the title compound. MS(m/z): 209 (M+1)⁺.

Thiazolo[4,5-c]pyridin-2-ylmethanol (R-4)

To a solution of ethyl thiazolo[4,5-c]pyridine-2-carboxylate (R-3) (5 g,24 mmol) in ethanol (100 mL) was added NaBH₄ (0.9 g, 24 mmol) inportions at 0° C. The suspension was stirred at room temperature for 1h, and then concentrated. The resulting residue was dissolved in EtOAc,washed with water. The organic layer was separated, dried over Na₂SO₄,concentrated in vacuo and purified by chromatography on silica gel togive the title compound. MS (m/z): 167 (M+1)⁺.

Thiazolo[4,5-c]pyridin-2-ylmethanamine (R)

Intermediate R was prepared from thiazolo[4,5-c]pyridin-2-ylmethanol(R-4) following similar procedures for synthesizing intermediate A fromA-3, as described above. MS (m/z): 165 (M)⁺.

Intermediate S

N-(2-Chloropyridin-3-yl)acetamide (S-2)

To a mixture of 3-chloropyridin-2-amine (S-1) (12.8 g, 100 mmol) andEt₃N (3 mL) in dried DCM (50 mL) was added acetyl chloride (8 mL)dropwise. The reaction was stirred at room temperature overnight, thenadjusted to pH about 7 with an aqueous NaHCO₃ solution, and extractedwith DCM. The organic layer was washed with water, dried over Na₂SO₄,and concentrated to afford the title compound (17.1 g). MS (m/z): 171.6(M+1)⁺.

2-Methylthiazolo[5,4-b]pyridine (S-3)

Intermediate S-3 was prepared from N-(2-chloropyridin-3-yl)acetamide(S-2) following similar procedures for synthesizing intermediate R-3from R-2, as described above. MS (m/z): 151.6 (M+1)⁺.

2-(Bromomethyl)thiazolo[5,4-b]pyridine (S-4)

Intermediate S-4 was prepared from 2-methylthiazolo[5,4-b]pyridine (S-3)following similar procedures for synthesizing intermediate B-5 from B-4,as described above.

Thiazolo[5,4-b]pyridin-2-ylmethanamine (S)

Intermediate S was prepared from 2-(bromomethyl)thiazolo[5,4-b]pyridine(S-4) following similar procedured for synthesizing intermediate C fromC-5, as described above. MS (m/z): 166 (M+1)⁺.

Intermediate T and T′

Methyl benzo[d]thiazole-6-carboxylate (T-2)

Intermediate T2 was prepared from benzo[d]thiazole-6-carboxylic acid(T-1) following similar procedures for synthesizing intermediate F-2from F-1, as described above.

Benzo[d]thiazol-6-ylmethanamine (T)

Intermediate T was prepared from methyl benzo[d]thiazole-6-carboxylate(T-2) following similar procedures for synthesizing intermediate D fromD-2, as described above. MS (m/z): 165 (M+1)⁺.

1-(Benzo[d]thiazol-6-yl)ethanamine (T′)

Intermediate T′ was prepared from benzo[d]thiazole-6-carboxylic acid(T-1) following similar procedures for synthesizing intermediate D′-5from D′-1, as described above, and intermediate D from D-4 as describedabove. MS (m/z): 179(M+1)⁺.

Synthesis of Boric Acid or Ester Intermediates Intermediate U

Tetrahydro-2H-pyran-4-yl methanesulfonate (U-2)

To a mixture of tetrahydro-2H-pyran-4-ol (U-1) (1.02 g, 10 mmol) andEt₃N (1 mL) in dried DCM (20 mL) was added MsCl (2 mL) dropwise. Thereaction was stirred at room temperature for 1 h, then washed withwater. The organic layer was separated, dried over Na₂SO₄, andconcentrated to afford the title compound (1.8 g).

4-Bromo-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole (U-3)

The mixture of tetrahydro-2H-pyran-4-yl methanesulfonate (U-2) (1.8 g,10 mmol), 4-bromo-1H-pyrazole (1.46 g, 10 mmol) and K₂CO₃(1.4 g, 10mmol) in DMF (10 mmol) was stirred at 80° C. overnight, then purified bychromatography to afford the title compound (861 mg). MS (m/z): 231(M+1)⁺.

1-(Tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(U)

To a mixture of 4-bromo-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole (U-3)(1.13 g, 4.48 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(861 mg, 3.73 mmol) and KOAc (12.43 g, 12.68 mmol) in DMSO (5 mL) wasadded Pd (dppf)Cl₂(172 mg, 0.21 mmol) under N₂. The mixture was stirredovernight at 80° C. under N₂. After cooling to room temperature, thereaction mixture was poured into water, and extracted with EtOAc. Theorganic phase was separated, concentrated in vacuo and then purified bychromatography to afford the title compound (170 mg). MS (m/z): 279(M+1)⁺.

Intermediate V

1-Ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (V)

To a solution of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (V-1) (3 g,15 mmol) in DMF (6 mL) were added bromoethane (3.24 g, 30 mmol) andK₂CO₃ (4.26 g, 30 mmol). The reaction mixture was stirred at 60° C.overnight, then diluted with EtOAc, washed with water and then brine.The organic layer was separated, then dried over Na₂SO₄, andconcentrated to afford the title compound (3.40 g). MS (m/z): 223(M+1)⁺.

Intermediate W

2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclopentanone(W-1)

Intermediate W-1 was prepared from 2-chlorocyclopentanone (1.06 g, 9mmol) following the similar procedures of synthesizing intermediate (V),as described above. MS (m/z): 277 (M+1)⁺.

2-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclopentanol(W)

To a solution of2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclopentanone(W-1) (550 mg, 2 mmol) in methanol (5 mL) was added NaBH₄ (150 mg, 4mmol). The reaction was stirred at room temperature for 1 h. The solventwas removed in vacuo, and the residue was extracted with EtOAc, washedwith water, and purified by chromatography on silica gel to afford thetitle compound (200 mg). MS (m/z): 279 (M+1)⁺.

Intermediate X

This intermediate was prepared from 4-bromo-1H-pyrazole as described inUS2007/0265272.

Other pyrazole boric acids or esters were prepared according to theprocedures of Intermediates (U-X)

Intermediate Y 2-(2,4-Dinitrophenoxy)isoindoline-1,3-dione (Y-2)

To a suspension of 2-hydroxyisoindoline-1,3-dione (20.0 g, 0.12 mol) inacetone (400 mL) was added Et₃N (14.9 g, 0.15 mol), the mixture wasstirred at room temperature until it became a homogeneous solution, then1-bromo-2,4-dinitrobenzene Y-1 (30.2 g, 0.12 mol) was added. Thereaction was stirred at room temperature for 3 h, then poured intoice-water, the resulting precipitate was filtered and washed three timeswith cold MeOH, dried in vacuum to afford the title compound (38.1 g).

2-(2,4-Dinitrophenyl)hydroxylamine (Y-3)

To a solution of 2-(2,4-dinitrophenoxy)isoindoline-1,3-dione Y-2 (20.0g, 60.7 mmol) in CH₂Cl₂ (400 ml) was added a solution of hydrazinehydrate (10.0 mL, 85%, 177 mmol) in MeOH (60 ml) at 0° C. The reactionmixture was stirred at 0° C. for 6 h, then treated with cold aqueous HCl(1N, 400 ml). The resulting mixture was rapidly filtered and washed withMeCN. The filtrate was transfered into a funnel. The organic phase wasseparated. The aqueous layer was extracted with CH₂Cl₂. The combinedorganic layers were dried over anhydrous Na₂SO₄, then concentrated toafford the title compound (7.9 g). MS (m/z): 183(M−16)⁻.

1-Amino-4-((tert-butyldimethylsilyloxy)methyl)pyridinium2,4-dinitrophenolate (Y-4)

To a solution of pyridin-4-ylmethanol (21.8 g, 0.20 mol) in CH₂Cl₂ (200mL) were added Et₃N (30.0 g, 0.30 mmol) and TBSCl (45.0 g, 0.30 mmol) at0° C. The reaction mixture was stirred at room temperature for 4 h, thenquenched with water. The organic phase was separated, and the aqueouslayer was extracted with CH₂Cl₂. The combined organic layers were washedwith brine, dried over Na₂SO₄ and concentrated. The residue was purifiedby silica gel chromatography to afford4-((tert-butyldimethylsilyloxy)methyl)-pyridine.

A mixture of 4-((tert-butyldimethylsilyloxy)methyl)pyridine (8.9 g, 39.7mmol) and O-(2,4-dinitrophenyl)hydroxylamine Y-3 (7.9 g, 39.7 mmol) inMeCN (27 ml) was stirred at 40° C. for 24 h, then concentrated to affordthe title compound (17.1 g), used in next step without furtherpurification. MS (m/z): 239(M−183)⁺.

Methyl5-((tert-butyldimethylsilyloxy)methyl)pyrazolo[1,5-a]pyridine-3-carboxylate(Y-5)

To a solution of1-amino-4-((tert-butyldimethylsilyloxy)methyl)pyridinium2,4-dinitrophenolate Y-4 (13.4 g, 31.6 mmol) in DMF (60 mL) were addedmethyl propiolate (2.7 g, 31.6 mmol) and K₂CO₃ (6.5 g, 47.4 mmol). Thereaction was stirred at room temperature for 24 h, then treated withwater. The resulting mixture was extracted with ethyl acetate (100ml×3), the combined organic layers were washed with water, brine anddried over Na₂SO₄, then concentrated in vacuo, the residue was purifiedby silica gel chromatography to afford the title compound (2.9 g). MS(m/z): 321 (M+1)⁺.

Methyl 5-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylate (Y-6)

To a solution of methyl5-((tert-butyldimethylsilyloxy)methyl)pyrazolo[1,5-a]pyridine-3-carboxylateY-5 (2.9 g, 9.1 mmol) in dry THF (20 mL) was added TBAF (3.5 g, 13.7mmol). The reaction mixture was stirred at room temperature for 10 mins,then treated with ethyl acetate. The resulting mixture was washed withbrine, dried over Na₂SO₄ and concentrated to afford the title compound(1.9 g).

Pyrazolo[1,5-a]pyridin-5-ylmethanol (Y-7)

A suspension of methyl5-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylate Y-6 (1.9 g, 9.1mmol) in 40% H₂SO₄ was stirred at 80° C. for 24 h, then neutralized with3N NaOH to pH=7-8. The resulting mixture was extracted with ethylacetate. The combined organic layers were washed with brine, dried overNa₂SO₄ and concentrated. The residue was purified by silica gelchromatography to afford the title compound (1.1 g). MS (m/z): 149(M+1)⁺.

Intermediate (Y)

Intermediate Y was prepared from pyrazolo[1,5-a]pyridin-5-ylmethanol(Y-7) following similar procedures for synthesizing intermediate D fromD-3.

Intermediate Z Methyl H-imidazo[1,2-a]pyridine-6-carboxylate (Z-2)

To a solution of Z-1 (9.0 g, 59.21 mmol) in anhydrous EtOH (160 ml) wasadded chloroacetaldehyde (40% in H₂O, 48.6 mL, 296 mmol). The reactionmixture was refluxed for 4 h, then concentrated. The residue wasdissolved in water and adjusted to pH>7 with a saturated NaHCO₃solution, extracted with EtOAc and purified by silica gel chromatographyto afford the title compound (6.60 g). MS (m/z): 177 (M+1)⁺.

N-Methoxy-N-methylH-imidazo[1,2-a]pyridine-6-carboxamide (Z-3)

To a mixture of Z-2 (5.0 g, 28.4 mmol) and N-methoxymethanamine (5.54 g,56.8 mmol) in dry THF (50 ml) at −20° C. under N₂ was addedisopropylmagnesium chloride (56.8 mL, 113.6 mmol) over 30 mins. Theresulting mixture was stirred at −20° C. for 30 mins, then quenched with20% NH₄Cl solution, and extracted with EtOAc (50 mL x3). The combinedorganic layers were dried over Na₂SO₄, concentrated and purified bysilicon gel chromatography to afford the title compound (3.0 g). MS(m/z): 206 (M+1)⁺.

1-(H-imidazo[1,2-a]pyridin-6-yl)ethanamine (Z)

It was prepared from compound Z-3 following similar procedures forsynthesizing intermediate D′ from D′-2.

Intermediate 1

Imidazo[1,2-b]pyridazine-6-carboxylic acid (1-2)

To a mixture of 6-aminopyridazine-3-carboxylic acid (1-1) (1.39 g, 10mmol) in ethanol in a sealed flask was added 2-chloroacetaldehyde (4 mL,40% aqueous). The reaction mixture was stirred at room temperature for 5min, then heated at 100° C. overnight. After cooled to room temperature,the mixture was concentrated to afford the title compound (1.63 g). MS(m/z): 164 (M+1)⁺

Methyl imidazo[1,2-b]pyridazine-6-carboxylate (1-3)

To a mixture of imidazo[1,2-b]pyridazine-6-carboxylic acid (1-2) (1.63g, 10 mmol) in SOCl₂ (15 mL) was added 10 drops of DMF at roomtemperature. The resulting solution was heated at reflux for 3 h. Aftercooled to room temperature, the reaction was concentrated, and theresulting solid was dissolved in methanol, and stirred for a while, thentreated with an aqueous saturated NaHCO₃ solution to pH7. The mixturewas purified by silica gel chromatography to afford the title compound(891 mg). MS (m/z): 178 (M+1)⁺

Imidazo[1,2-b]pyridazin-6-ylmethanol (1-4)

To a solution of methyl imidazo[1,2-b]pyridazine-6-carboxylate (1-3)(891 mg, 5.03 mmol) in ethanol (25 mL) was added NaBH₄ (420 mg, 11.1mmol) at room temperature. The suspension was stirred at roomtemperature for 2 h. The reaction mixture was concentrated in vacuum.The residue was purified by chromatography on silica gel to afford thetitle compound (630 mg). MS (m/z): 150 (M+1)⁺

Imidazo[1,2-b]pyridazin-6-ylmethanamine (Intermediate 1)

Intermediate 1 was prepared from imidazo[1,2-b]pyridazin-6-ylmethanol(1-4) following the procedures similar to procedure of intermediate Dfrom D-3. MS (m/z): 149 (M+1)⁺

Intermediate 2

Pyrazolo[1,5-a]pyrimidine-5-carbonitrile (2-2)

To a mixture of 5-chloropyrazolo[1,5-a]pyrimidine (2-1) (1.0 g, 6.45mmol) and Zn(CN)₂ (770 mg, 6.58 mmol) in dried DMF (20 mL) exchanged byN₂ was added Pd(PPh₃)₄ (400 mg, 3.46 mmol). The reaction mixture wasstirred at 110° C. overnight. After cooled to the room temperature, thesolution was concentrated and purified by chromatography on silica gelto afford the title compound (620 mg)

Pyrazolo[1,5-a]pyrimidin-5-ylmethanamine (Intermediate 2)

To a solution of pyrazolo[1,5-a]pyrimidine-5-carbonitrile (2-2) (620 mg,4.31 mmol) in NH₃ in MeOH (5 mL) was added Raney Ni (100 mg). Thereaction mixture was stirred at room temperature for 3 h under H₂. Themixture was filtered, and the filtrate was concentrated to afford thetitle compound (600 mg). MS (m/z): 149 (M+1)⁺.

Intermediate 3 3-1

To a solution of 1-(pyridin-4-yl)ethanone (100 mg, 0.82 mmol) dissolvedin CH₃CN (3 mL) was added Y-3 (180 mg, 0.9 mmol). The reaction mixturewas heated to 40° C. and stirred at 40° C. for 24 h. Solvent was removedin vacuum. The residue was used in next step without furtherpurification (225 mg).

Methyl 5-acetylpyrazolo[1,5-a]pyridine-3-carboxylate (3-2)

To a mixture of (3-1) (100 mg, 0.31 mmol) and K₂CO₃ (60 mg, 0.43 mmol)in DMF (1 mL) was added methyl propiolate (29 mg, 0.34 mmol) dropwise.The reaction mixture was stirred vigorously at room temperature for 24h. The suspension was filtered. The filtrate was concentrated. Theresulting residue was dissolved in Et₂O and washed with water. Theorganic layer was separated, concentrated and purified by chromatographyon silica gel to afford the title compound (20 mg). MS (m/z): 219(M+1)⁺.

1-(Pyrazolo[1,5-a]pyridin-5-yl)ethanone (3-3)

A suspension of methyl 5-acetylpyrazolo[1,5-a]pyridine-3-carboxylate(3-2) (90 mg, 0.41 mmol) dissolved in 50% H₂SO₄ (2 mL) was stirred at80° C. for 3 h. After cooled to 0° C., the solution was treated with 5NNaOH solution, and then extracted with Et₂O. The organic layer wasseparated, dried, concentrated and purified by flash chromatography toafford the title compound (25 mg).

1-(Pyrazolo[1,5-a]pyridin-5-yl)ethanamine (Intermediate 3)

Intermediate 3 was prepared from 1-(pyrazolo[1,5-a]pyridin-5-yl)ethanone(3-3) following the procedures similar to the procedures of intermediateD′ from D′-3. MS (m/z): 162 (M+1)⁺.

Intermediate 4

N-(4-(Chloromethyl)pyridin-2-yl)-N′-hydroxyformimidamide (4-2)

To a solution of 4-(chloromethyl)pyridin-2-amine (4-1) (1.56 g, 8.7mmol) in propan-2-ol (15 mL) was added DMF-DMA (1.56 mL, 11.3 mmol) atroom temperature under N₂. The reaction mixture was heated to 90° C. for3 h. After cooled to 50° C., the mixture was treated with NH₂OH.HCl(0.781 g, 11.3 mmol), then stirred at 50° C. overnight. After cooled toroom temperature, the mixture was concentrated and purified bychromatography on silica gel to afford the title compound (820 mg). MS(m/z): 186 (M+1)⁺.

7-(Chloromethyl)-[1,2,4]triazolo[1,5-a]pyridine (4-3)

To a solution ofN-(4-(chloromethyl)pyridin-2-yl)-N′-hydroxyformimidamide (4-2) (820 mg,4.4 mmol) in anhydrous THF (5 mL) cooled to 0° C. was added TFAA (1.1 g,5.28 mmol) dropwise under N₂. The reaction mixture was stirred at roomtemperature for 3 h. Then the mixture was treated with aqueous NaHCO₃ topH 8, concentrated and purified by chromatography on silica gel toafford the title compound (400 mg). MS (m/z): 168 (M+1)⁺.

7-(Azidomethyl)-[1,2,4]-triazolo[1,5-a]pyridine (4-4)

To a solution of 7-(chloromethyl)-[1,2,4]triazolo[1,5-a]pyridine (4-3)(400 mg, 2.4 mmol) in dried DMF (5 mL) was added NaN₃ (250 mg, 3.6 mmol)under N₂. The reaction mixture was stirred at 80° C. for 2 h, thenquenched with aqueous Na₂S₂O₃. The resulting mixture was extracted withEtOAc, dried on Na₂SO₄, and concentrated to afford the title compound(340 mg), which was used in next step without further purification. MS(m/z): 175 (M+1)⁺.

[1,2,4]Triazolo[1,5-a]pyridin-7-ylmethanamine (Intermediate 4)

To a solution of 7-(azidomethyl)-[1,2,4]triazolo[1,5-a]pyridine (4-4)(340 mg, 1.9 mmol) in methanol (20 mL) was added Pd/C (30 mg). Thereaction mixture was stirred at room temperature under H₂ (1 atm) for 2h. The mixture was filtered to remove Pd/C. The filtrate wasconcentrated to afford the title compound (300 mg) MS (m/z): 149 (M+1)⁺.

Intermediate 5

Imidazo[1,2-a]pyrazine-6-carbonitrile (5-2)

To a solution of 5-aminopyrazine-2-carbonitrile (5-1) (350 mg, 2.92mmol) in ethanol (15 mL) was added 2-chloroacetaldehyde (4 mL, 40% inwater). The mixture was stirred at 110° C. overnight. The solution wasconcentrated, then purified by chromatography on silica gel to affordthe title compound (280 mg). MS (m/z): 145.1 (M+H)⁺.

Imidazo[1,2-a]pyrazin-6-ylmethanamine (Intermediate 5)

To a solution of imidazo[1,2-a]pyrazine-6-carbonitrile (5-1) (180 mg,1.25 mmol) in methanol (15 mL) were added Raney nickel (slurry in water,150 mg) and 1 N ammonia. The reaction mixture was stirred under H₂ (1atm) for 2 h. The mixture was filtered, and the filtrate wasconcentrated to afford the title compound (160 mg). MS (m/z): 149.1(M+H)⁺

Intermediate 6

2-Bromopropanal (6-1)

To a solution of propionaldehyde (20 mL, 265 mmol) in 25 mL of dioxaneat 0° C. was added bromine (13.5 mL, 265 mmol) within 1 h. The reactionmixture was allowed to continue stirring for an additional 10 min untilthe reaction became colorless. The mixture was diluted with 200 mL ofether, and washed with aqueous NaHSO₄, NaHCO₃ and brine. The aqueouslayer was extracted with ether. The combined organic layer was driedover Na₂SO₄ and concentrated. The resulting oil was further purified bydistillation under vacuum to afford the title compound (8.5 g).

3-Methylimidazo[1,2-a]pyridine-6-carbonitrile (6-2)

To a solution of 6-aminonicotinonitrile (1.2 g, 10.1 mmol) in ethanol(80 mL) was added 2-bromopropanal (6-1) (6.9 g, 50.5 mmol). The reactionmixture was stirred at 80° C. overnight. The solution was concentrated,diluted with water (20 mL) and adjusted to PH>7 with saturated aqueousNaHCO₃ solution. The precipitate was collected to afford the titlecompound (430 mg). MS (m/z): 158 (M+H)⁺.

3-Methylimidazo[1,2-a]pyridin-6-yl)methanamine (Intermediate 6

To a solution of 3-methylimidazo[1,2-a]pyridine-6-carbonitrile (6-2)(200 mg, 1.27 mmol) in methanol (30 mL) were added Raney nickel (slurryin water, 100 mg) and 1N ammonia. The reaction mixture was stirred underH₂ for 2 h, then filtered and concentrated to afford the title compound(200 mg). MS (m/z): 162 (M+H)⁺

Intermediate 7

3-(Hydroxymethyl)imidazo[1,2-a]pyridine-6-carbonitrile (7-2)

To a solution of imidazo[1,2-a]pyridine-6-carbonitrile (7-1) (1.43 g, 10mmol) in 3 mL of acetic acid were added sodium acetate (3.03 g, 37 mmol)and then formaldehyde (6 mL, 37% in water). The reaction mixture wasstirred at 100° C. overnight. After cooled to room temperature, themixture was adjusted to pH>7 with aqueous Na₂CO₃. The precipitate wascollected to afford the title compound (1.4 g). MS (m/z): 174.0 (M+H)⁺

3-(Methoxymethyl)imidazo[1,2-a]pyridine-6-carbonitrile (7-3)

To a solution of 3-(hydroxymethyl)-imidazo[1,2-a]pyridine-6-carbonitrile(7-2) (346 mg, 2 mmol) in 20 mL of THF was added sodium hydride (240 mg,60% in oil) at 0° C. The reaction mixture was stirred at 0° C. for 1 h,then methyl iodide (615 mg, 4.3 mmol) was added. The reaction wasstirred at room temperature overnight. The mixture was treated withaqueous Na₂CO₃, then concentrated. The residue was diluted with waterand extracted with EtOAc. The combined organics were dried over Na₂SO₄and concentrated to afford the title compound (300 mg). MS (m/z): 188.0(M+H)⁺

3-(Methoxymethyl)imidazo[1,2-a]pyridin-6-yl)methanamine (Intermediate 7

To a solution of 3-(methoxymethyl)imidazo[1,2-a]pyridine-6-carbonitrile(7-3) (300 mg, 1.6 mmol) in methanol (30 mL) were added Raney nickel(slurry in water, 150 mg) and 1N ammonia. The reaction mixture wasstirred under H₂ for 2 h. The mixture was filtered. The filtrate wasconcentrated to afford the title compound (300 mg). MS (m/z): 192.0(M+H)⁺

Intermediate 8

2-Methyl-1,5-naphthyridine (8-2)

A mixture of 6-methylpyridin-3-amine (8-1) (4.8 g, 44.4 mmol) andpropane-1,2,3-triol (20 g, 222 mmol) in 5 mL of H₂O was stirred at roomtemperature for 5 min, then concentrated H₂SO₄ (47 g, 488 mmol) wasadded dropwise within 20 min at room temperature. After addition, thereaction mixture was stirred at 150° C. for 30 min. After cooled to roomtemperature, the mixture was poured into water, adjusted with 6 N NaOHto pH 13, then extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over Na₂SO₄, concentrated and purified bychromatography on silica gel to afford the title compound (2.9 g). MS:145 (M+1)⁺.

1,5-Naphthyridine-2-carbaldehyde (8-3)

A mixture of 2-methyl-1,5-naphthyridine (8-2) (2.9 g, 20.1 mmol) andSeO₂(2.2 g, 20.1 mmol) in 40 mL of dioxane was refluxed for 3 h. Aftercooled to room temperature, the reaction mixture was concentrated. Theresidue was treated with brine and extracted with DCM/i-PrOH=4/1. Theorganic layer was washed with brine, dried over Na₂SO₄, concentrated andpurified by chromatography on silica gel to afford the title compound(1.81 g).

1,5-Naphthyridin-2-yl)methanol (8-4

To a solution of 1,5-naphthyridine-2-carbaldehyde (8-3) (1.0 g, 6.32mmol) in MeOH (15 mL) and THF (15 mL) was added NaBH₄ (84 mg, 2.21mmol). The reaction mixture was stirred at 0° C. for 0.5 h. The mixturewas concentrated and purified by chromatography on silica gel to affordthe title compound (790 mg).

1,5-Naphthyridin-2-yl)methanamine (Intermediate 8

Intermediate 8 was prepared from (1,5-naphthyridin-2-yl)methanol (8-4)following the procedures similar to the procedure for synthesizingintermediate D from D-3. MS (m/z): 160 (M+1)⁺.

Intermediate 9

Methyl 5-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylate (9-1)

To a solution of methyl5-((tert-butyldimethylsilyloxy)methyl)pyrazolo[1,5-a]pyridine-3-carboxylate(Y-5) (2.9 g, 9.1 mmol) in anhydrous THF (20 mL) was added TBAF (3.5 g,13.7 mmol). The reaction mixture was stirred at room temperature for 10min, then treated with ethyl acetate (50 mL). The resulting mixture waswashed with brine, dried over Na₂SO₄ and concentrated to afford thetitle compound (1.9 g).

Methyl 5-(aminomethyl)pyrazolo[1,5-a]pyridine-3-carboxylate(intermediate 9)

Intermediate 9 was prepared from methyl5-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylate (9-1) followingthe procedures similar to the procedure of synthesizing intermediate Dfrom D-3. MS (m/z): 148 (M+1)⁺.

Intermediate 10

1H-Thieno[3,2-c]pyrazole-5-carboxylic acid (10-1)

To a solution of methyl 1H-thieno[3,2-c]pyrazole-5-carboxylate (F-5)(4.2 g, 18.7 mmol) in MeOH (50 mL) was added a solution of LiOH.H₂O (3.1g, 74.8 mmol) in water (5 mL). The reaction mixture was stirred at roomtemperature overnight. Then 1N HCl was added to adjust to pH to ˜5, theresulting precipitate was collected and dried to afford the titlecompound.

1-(1H-thieno[3,2-c]pyrazol-5-yl)ethanamine (intermediate 10)

Intermediate 10 was prepared from 1H-thieno[3,2-c]pyrazole-5-carboxylicacid (10-1) following similar procedures for synthesizing intermediateT′ from T-1. MS (m/z): 168 (M+1)⁺.

Intermediate 11

1-(imidazo[1,2-a]pyridin-6-yl)propan-1-amine

Intermediate 11 was prepared from Z-3 following similar procedures forsynthesizing intermediate Z from Z-3.

Example 1 Preparation of Compounds 1-332

Compounds of the present invention can be made according to thefollowing examples. It will be understood by those skilled in the artthat the following examples do not limit the invention. For example, itmay be possible to alter exact solvents, conditions, quantities, orutilize the equivalent reagents and intermediates with appropriateprotecting groups.

Compound 1,1-((1H-Pyrrolo[2,3-b]pyridin-3-yl)methyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]-triazolo[4,5-b]pyrazine

N²-((1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-6-bromopyrazine-2,3-diamine

A mixture of (1H-pyrrolo[2,3-b]pyridin-3-yl)methanamine (intermediate A)(442 mg, 3.0 mmol), 3,5-dibromopyrazin-2-amine (758 mg, 3.0 mmol) andN-ethyl-N-isopropylpropan-2-amine (1160 mg, 9.0 mmol) in EtOH (70 mL)was stirred at 150° C. overnight. After being cooled to roomtemperature, it was concentrated and purified by chromatography toafford the title compound (70 mg) MS (m/z): 319 (M+1)⁺.

1-((1H-Pyrrolo[2,3-b]pyridin-3-yl)methyl)-6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazine

To the ice-cooled mixture ofN²-((1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-6-bromopyrazine-2,3-diamine(48 mg, 0.15 mmol) in HOAc/H₂O (1.5 mL/1.5 mL) was added NaNO₂ (31 mg,0.45 mmol) in water (0.2 mL). The reaction was stirred for 1.5 h in anice bath, then aqueous H₂SO₄ (49%, 0.1 mL) was added. The resultingmixture was allowed to warm to room temperature and stir overnight, thenwas adjusted to pH>8 with 3 N aqueous NaOH solution, and extracted withEtOAc. The combined organics were dried over Na₂SO₄, filtered andconcentrated to give the title compound (46 mg) MS (m/z): 332 (M+1)⁺.

1-((1H-Pyrrolo[2,3-b]pyridin-3-yl)methyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]-triazolo[4,5-b]pyrazine

The mixture of1-((1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-6-bromo-1H-[1,2,3]triazolo-[4,5-b]pyrazine(46 mg, 0.14 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (77mg, 0.35 mmol), PdCl₂(dppf) (12 mg, 0.014 mmol) and Cs₂CO₃ (137 mg, 0.42mmol) in dioxane/H₂O (10:1, 8 mL) was stirred at 80° C. overnight. Afterbeing cooled to room temperature, the mixture was concentrated andpurified by chromatography to afford the title compound (18 mg) MS(m/z): 332 (M+H).

Compounds 2-59, 265-269, 272, 274-277, 279-290, 293-296, 298-299,301-305, 308-310,316-317, 326, 328-329, 331

The following compounds 2-59, 265-269, 272, 274-277, 279-290, 293-296,298-299, 301-305, 308-310, 316-317, 326, 328-329, 331 were preparedaccording to the procedures of Compound 1 using the correspondingintermediates and boronic acid or ester under appropriate conditionsthat will be recognized by one skilled in the art:

TABLE 1 Compound Structure LC/MS data  2

349 (M + 1)⁺  3

332 (M + 1)⁺  4

358 (M + 1)⁺  5

379 (M + 1)⁺  6

351 (M + 1)⁺  7

379 (M + 1)⁺  8

346 (M + 1)⁺  9

362 (M + 1)⁺  10

362 (M + 1)⁺  11

349 (M + 1)⁺  12

379 (M + 1)⁺  13

367.4 (M)⁺  14

348 (M)⁺  15

377 (M + 1)⁺  16

362 (M + 1)⁺  17

407 (M + 1)⁺  18

418 (M + 1)⁺  19

363 (M + 1)⁺  20

393 (M + 1)⁺  21

393 (M + 1)⁺  22

419 (M + 1)⁺  23

393 (M + 1)⁺  24

432 (M + 1)⁺  25

352 (M + 1)⁺  26

366 (M + 1)⁺  27

363 (M + 1)⁺  28

349 (M + 1)⁺  29

377 (M + 1)⁺  30

379 (M + 1)⁺  31

366 (M + 1)⁺  32

396.7 (M + 1)⁺  33

332 (M + 1)⁺  34

360 (M + 1)⁺  35

357 (M + 1)⁺  36

362 (M + 1)⁺  37

380 (M + 1)⁺  38

396 (M + 1)⁺  39

391.7 (M + 1)⁺  40

394.5 (M + 1)⁺  41

363 (M + 1)⁺  42

406.9 (M + 1)⁺  43

338 (M + 1)⁺  44

324 (M + 1)⁺  45

382 (M + 1)⁺  46

401 (M + 1)⁺  47

360 (M + 1)⁺  48

400 (M + 1)⁺  49

347 (M + 1)⁺  50

363 (M + 1)⁺  51

333 (M + 1)⁺  52

401 (M + 1)⁺  53

377 (M + 1)⁺  54

363 (M + 1)⁺  55

403 (M + 1)⁺  56

354 (M + 1)⁺  57

358 (M + 1)⁺  58

376 (M + 1)⁺  59

359 (M + 1)⁺ 265

362 (M + 1)⁺ 266

332 (M + 1)⁺ 267

400 (M + 1)⁺ 268

376 (M + 1)⁺ 269

346 (M + 1)⁺  272*

362 (M + 1)⁺ 274

333.1 (M + 1)⁺ 275

329.1 (M + 1)⁺ 276

359 (M + 1)⁺ 277

413.9 (M + 1)⁺ 279

333 (M + 1)⁺ 280

401 (M + 1)⁺ 281

363.1 (M + 1)⁺ 282

360.1 (M + 1)⁺ 283

379.0 (M + 1)⁺ 284

332.9 (M + 1)⁺ 285

333 (M + 1)⁺ 286

374.1 (M + 1)⁺ 287

400.9 (M + 1)⁺ 288

363.0 (M + 1)⁺ 289

350 (M + 1)⁺ 290

373 (M + 1)⁺ 293

401 (M + 1)⁺ 294

333 (M + 1)⁺ 295

335.9 (M + 1)⁺ 296

380.0 (M + 1)⁺ 298

346 (M + 1)⁺ 299

351.9 (M + 1)⁺ 301

357.0 (M + 1)⁺ 302

354.1 (M + 1)⁺ 303

346.1 (M + 1)⁺ 304

420.0 (M + 1)⁺ 305

376.0 (M + 1)⁺ 308

376.0 (M + 1)⁺ 309

405.9 (M + 1)⁺ 310

375.9 (M + 1)⁺ 316

333.0 (M + 1)⁺ 317

362.9 (M + 1)⁺ 326

360.1 (M + 1)⁺ 328

332.1 (M + 1)⁺ 329

466.1 (M + 1)⁺ 331

346 (M + 1)⁺

Compound 272 was prepared from Compound 33 by the following procedure:

To a solution of compound 33 (66 mg, 0.2 mmol) in 0.1 mL of acetic acidwere added sodium acetate (60 mg, 0.73 mmol) and an aqueous solution offormaldehyde (37%, 0.2 mL, 2.8 mmol). The reaction mixture was stirredat 100° C. overnight. After cooled to room temperature, the reactionmixture was diluted with water and basified with a saturated sodiumcarbonate aqueous solution. The resulting precipitate was filtered. Thefiltrate was purified by chromatography to afford compound 272 (30 mg).

Compound 60:

3-Nitro-6-chloro-N-(thiazolo[4,5-c]pyridin-2-ylmethyl)pyridin-2-amine

To a solution of 3-nitro-2,6-dichloropyridine (106 mg, 0.55 mmol) inisopropanol (3 mL) was sequentially added Na₂CO₃ (116 mg, 1.1 mmol) andintermediate R (100 mg, 0.61 mmol). The reaction mixture was stirred atroom temperature overnight, and then concentrated. The residue wasextracted with EtOAc. The organic layer was separated, concentrated, andpurified by chromatography on silica gel to afford the title compound.MS (m/z): 322 (M)⁺.

6-Chloro-N²-(thiazolo[4,5-c]pyridin-2-ylmethyl)pyridine-2,3-diamine

10% Pd/C (20 mg) was added to a solution of3-nitro-6-chloro-N-(thiazolo[4,5-c]pyridin-2-ylmethyl)pyridin-2-amine(100 mg, 0.31 mmol) in MeOH (2 mL) and THF (10 mL). The mixture wasstirred at room temperature under 1 atm of H₂ for 1 h, and thenfiltered. The filtrate was concentrated and purified by chromatographyon silica gel to afford the title compound. MS (m/z): 292 (M+1)⁺.

5-Chloro-3-(thiazolo[4,5-c]pyridin-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridine

A solution of NaNO₂ (42.5 mg, 0.62 mmol) in H₂O (0.5 mL) was addeddropwise to a solution of6-chloro-N²-(thiazolo[4,5-c]pyridin-2-ylmethyl)pyridine-2,3-diamine (90mg, 0.31 mmol) in AcOH (1 mL) and H₂O (1 mL) at 0° C. The reactionsolution was stirred at 0° C. for 1 h, then basified with 30% aqueousNaOH to pH ˜9. The resulting precipitate was collected by filtration toafford the title compound. MS (m/z): 303 (M+1)⁺.

5-(1-(2-(Tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)-3-(thiazolo[4,5-c]pyridin-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridine

To a solution of intermediate X (75 mg, 0.23 mmol),5-chloro-3-(thiazolo[4,5-c]pyridin-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridine(64 mg, 0.21 mmol) in dioxane (1.5 mL) and H₂O (0.15 mL) were addedPd(dppf)Cl₂ (32.7 mg, 0.04 mmol) and Cs₂CO₃ (98 mg, 0.3 mmol) under N₂.The resulting mixture was stirred at 120° C. overnight under N₂, andthen concentrated. The residue was purified by chromatography to affordthe title compound. MS (m/z): 463 (M+1)⁺.

2-(4-(3-(Thiazolo[4,5-c]pyridin-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-1H-pyrazol-1-yl)ethanol

5-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)-3-(thiazolo[4,5-c]pyridin-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridine(20 mg, 0.04 mmol) was dissolved in MeOH/HCl (2 mL). The reactionmixture was stirred at room temperature for 1 h, and then concentrated.The residue was purified by chromatography to afford the title compound.MS (m/z): 379 (M+1)⁺.

Compounds 61-76, 79, 81-151, 273, 291, 292, 297, 332

The following compounds 61-76, 79, 81-151, 273, 291, 292, 297, 332 wereprepared according to the procedures of Compound 60 using thecorresponding intermediates and boronic acid or ester under appropriateconditions that will be recognized by one skilled in the art:

TABLE 2 Compound Structure LC/MS data  61

372 (M + 1)⁺  62

354 (M + 1)⁺  63

424 (M + 1)⁺  64

327 (M + 1)⁺  65

414 (M + 1)⁺  66

386 (M + 1)⁺  67

348 (M + 1)⁺  68

378 (M + 1)⁺  69

419 (M + 1)⁺  70

369 (M + 1)⁺  71

348 (M + 1)⁺  72

348 (M + 1)⁺  73

378 (M + 1)⁺  74

378 (M + 1)⁺  75

331 (M + 1)⁺  76

368 (M + 1)⁺  79

353 (M + 1)⁺  81

328 (M + 1)⁺  82

412 (M + 1)⁺  83

396 (M + 1)⁺  84

431 (M + 1)⁺  85

431 (M + 1)⁺  86

361 (M + 1)⁺  87

344 (M + 1)⁺  88

368 (M + 1)⁺  90

432 (M + 1)⁺  91

396 (M + 1)⁺  92

399 (M + 1)⁺  93

386 (M + 1)⁺   94¹

411 (M + 1)⁺  95

356 (M + 1)⁺  96

412 (M + 1)⁺  97

412 (M + 1)⁺   98²

414 (M + 1)⁺  99

413 (M + 1)⁺ 100

386 (M + 1)⁺  101³

425 (M + 1)⁺ 102

369 (M + 1)⁺ 103

364 (M + 1)⁺  104⁴

374 (M + 1)⁺  105⁵

401 (M + 1)⁺ 106

375 (M + 1)⁺ 107

413 (M + 1)⁺  108⁶

342 (M + 1)⁺  109⁶

372 (M + 1)⁺ 110

412 (M + 1)⁺ 111

375 (M + 1)⁺ 112

357 (M + 1)⁺ 113

375 (M + 1)⁺ 114

376 (M + 1)⁺ 115

385 (M + 1)⁺ 116⁷

400 (M + 1)⁺ 117

367 (M + 1)⁺ 118

412 (M + 1)⁺ 119

412 (M + 1)⁺ 120

332 (M + 1)⁺ 121

400 (M + 1)⁺ 122

368 (M + 1)⁺ 123

398 (M + 1)⁺ 124

378 (M + 1)⁺ 125

348 (M + 1)⁺ 126

362 (M + 1)⁺ 127

360 (M + 1)⁺ 128

390 (M + 1)⁺ 129

360 (M + 1)⁺ 130

390 (M + 1)⁺ 131

356 (M + 1)⁺ 132

337 (M + 1)⁺ 133

331 (M + 1)⁺ 134

361 (M + 1)⁺ 135

345 (M + 1)⁺ 136

359 (M + 1)⁺ 137

346 (M + 1)⁺ 138⁸

362 (M + 1)⁺ 139

379 (M + 1)⁺ 140

359 (M + 1)⁺ 141

399 (M + 1)⁺ 142

349 (M + 1)⁺ 143

401 (M + 1)⁺ 144

370 (M + 1)⁺ 145

328 (M + 1)⁺ 146

370 (M + 1)⁺ 147

410 (M + 1)⁺  148⁹

379 (M + 1)⁺  149⁹

349 (M + 1)⁺ 150

406 (M + 1)⁺ 151

332 (M + 1)⁺ 273

362.1 (M + 1)⁺ 291

343.1 (M + 1)⁺ 292

411 (M + 1)⁺ 297

373.1 (M + 1)⁺ 332

386 (M + 1)⁺ ¹Using the following procedure, Compound 94 was synthesizedfrom intermediate 94-a that was prepared according to the procedures ofCompound 60 using the corresponding intermediates and boronic acid orester under appropriate conditions that will be recognized by oneskilled in the art. :

A solution of 94-a (30 mg, 0.06 mmol) in TFA (2 mL) and DCM (2 mL) wasstirred at room tempature overnight, then concentrated. The residue wasdissolved in aqueous sodium bicarbonate solution and extracted withEtOAc. The organic layer was concentrated and purified on silica gel toafford Compound 94. ²Compound 98 was prepared from Compound 61 using thefollowing procedure:

A solution of Compound 61 in DCM was treated with Et₃N and acetylchloride at room temparature for 3 h. It was then treated with water andextracted with DCM (15 mL × 2). The combined organic extracts weredried, concentrated and the residue was purified on silica to affordCompound 98. ³Compound 101 was prepared from Compound 94 using thefollowing procedure: To a solution of Compound 94 (18 mg, 0.044 mmol) inanhydrous DCM (2 mL) was added Et₃N (12.2 uL, 0.088 mmol), followed byCH₃I (2.4 uL, 0.048 mmol) at 0° C. The reaction mixture was warmed toroom tempature, and stirred for over 1 h. A saturated sodium bicarbonateaqueous solution was added to the mixture. The organic layer wasseparated, and the aqueous layer was extracted with EtOAc. The combinedextracts were dried over Na₂SO₄ and concentrated. The resulting residuewas purified on silica to afford Compound 101. ⁴Compound 104 wasprepared according to the procedure of Intermediates W-1 to W usingIntermediate 104-a that was prepared according to the procedures ofCompound 60.

⁵Compound 105 was prepared from intermediate 104-a by the followingprocedure

A mixture of intermediate 104-a (37 mg, 0.1 mmol) and exessive amount ofdimethylamine in methanol (5 mL) was stirred at room temperature for 1h. Sodium cyano borohydride (12 mg) was added. The resulting mixture wasstirred at room temperature for 16 h, then concentrated. The residue wastreated with saturated aqueous sodium bicarbonate and DCM. The organiclayer was separated, concentrated. The residue was purified on silica toafford Compound 105 (8 mg). ⁶Under similar conditions of Compound 60,Compound 108 was prepared by using Intermediate 108-a that was preparedaccording to the procedure of intermediates U-3 to U

Compound 109 was prepared similar to Compound 108 ⁷Compound 116 wasprepared according to the procedures of Compound 94. ⁸P(t-Bu)₃HBF₄ andPd₂(dba)₃ were used instead of Pd(dppf)Cl₂ in the procedure of Compound138. ⁹Compounds 148 was prepared by the following route using similarconditions described for Compound 60.

According to the procedure of Compound 148, Compound 149 was preparedusing the corresponding intermediates and reagents under appropriateconditions that will be recognized by one skilled in the art:

Compound 152:N-(1-methyl-1H-pyrazol-3-yl)-1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo-[4,5-b]pyracin-6-amine

To a suspension of6-((6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline (68mg, 0.2 mmol) (prepared from quinolin-6-ylmethanamine following theprocedures of Compound 1) and 1-methyl-1H-pyrazol-3-amine (20 mg, 0.22mmol) in dioxane (5 mL) were added Cs₂CO₃ (72 mg, 0.22 mmol) and H₂O(0.5 mL). The mixture was degassed and charged with N₂ three times, thenPd₂(dba)₃ (0.02 mmol, 18 mg) and xantphos (0.04 mmol, 23 mg) were added.The resulting mixture was stirred at 120° C. under one atmosphere of N₂overnight, then concentrated. The resulting residue was purified bychromatography to afford the title compound (10 mg). MS (m/z): 358(M+1)⁺.

Compounds 80, 153-240

The following compounds 80, 153-240 were prepared according to theprocedure of Compound 152 using the corresponding intermediates andamines under appropriate conditions that will be recognized by oneskilled in the art:

TABLE 3 Compound Structure LC/MS data  80

328 (M + 1)⁺ 153

389 (M + 1)⁺ 154¹⁰

383 (M + 1)⁺ 155

369 (M + 1)⁺ 156

385 (M + 1)⁺ 157

369 (M + 1)⁺ 158

369 (M + 1)⁺ 159

399 (M + 1)⁺ 160

359 (M + 1)⁺ 161

360 (M + 1)⁺ 162

385 (M + 1)⁺ 163

369 (M + 1)⁺ 164

389 (M + 1)⁺ 165

440 (M + 1)⁺ 166

440 (M + 1)⁺ 167

440 (M + 1)⁺ 168

355 (M + 1)⁺ 169

355 (M + 1)+ 170

393 (M + 1)⁺ 171

393 (M + 1)⁺ 172

375 (M + 1)⁺ 173

358 (M + 1)⁺ 174

412 (M + 1)⁺ 175

412 (M + 1)⁺ 176

375 (M + 1)⁺ 177¹⁰

369 (M + 1)⁺ 178

384 (M + 1)⁺ 179

384 (M + 1)⁺ 180

384 (M + 1)⁺ 181

368 (M + 1)+ 182

368 (M + 1)⁺ 183

385 (M + 1)⁺ 185

429 (M + 1)⁺ 186

429 (M + 1)⁺ 187

384 (M + 1)⁺ 188

369 (M + 1)⁺ 189

357 (M + 1)+ 190

380 (M + 1)⁺ 191

358 (M + 1)⁺ 192

412 (M + 1)⁺ 193

440 (M + 1)⁺ 194

415 (M + 1)⁺ 195

385 (M + 1)⁺ 196

369 (M + 1)⁺ 197

385 (M + 1)⁺ 198

344 (M + 1)⁺ 199

359 (M + 1)⁺ 200

359 (M + 1)⁺ 201

415 (M + 1)⁺ 202

427 (M + 1)⁺ 203

428 (M + 1)⁺ 204

428 (M + 1)⁺ 205

414 (M + 1)⁺ 206

454 (M + 1)⁺ 207

454 (M + 1)⁺ 208

429 (M + 1)⁺ 209

428 (M + 1)+ 210

385 (M + 1)⁺ 211

429 (M + 1)⁺ 212

355 (M + 1)⁺ 213

385 (M + 1)⁺ 214

328 (M + 1)⁺ 215

379 (M + 1)⁺ 216

429 (M + 1)⁺ 217

441 (M + 1)⁺ 218

441 (M + 1)⁺ 219

453 (M + 1)⁺ 220

423 (M + 1)⁺ 221

423 (M + 1)⁺ 222

440 (M + 1)⁺ 223

380 (M + 1)⁺ 224

383 (M + 1)⁺ 225

379 (M)⁺ 226

455 (M + 1)⁺ 227

428 (M)⁺ 228

456 (M + 1)⁺ 229

453 (M + 1)⁺ 230

440 (M + 1)⁺ 231

384 (M + 1)⁺ 232

447 (M + 1)⁺ 233

427 (M)⁺ 234

384 (M + 1)⁺ 235

368 (M + 1)⁺ 236

354 (M + 1)⁺ 237

354 (M + 1)⁺ 238

379 (M + 1)⁺ 239¹⁰

394 (M + 1)⁺ 240

394 (M + 1)⁺ 241

361 (M + 1)⁺ 242

361 (M + 1)⁺ 243

361 (M + 1)⁺ ¹⁰Under similar conditions described in Compound 152,Compound 154 was synthesized by using Intermediate 154-a that wasprepared according to the procedure of Compound 244, under appropriateconditions that will be recognized by one skilled in the art.

According to the procedure of Compound 154, Compound 177 and 239 wereprepared using the corresponding intermediates and reagents underappropriate conditions that will be recognized by one skilled in theart.

Compound 244:6-((6-(Pyridin-4-ylthio)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)-quinoline

The mixture6-((5-chloro-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline (60mg, 0.2 mmol) (prepared according to Compound 60), Cs₂CO₃ (195 mg, 0.6mmol) and 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride (52 mg,0.3 mmol) in DMF (1.5 mL) was stirred at 120° C. overnight, thenconcentrated. The residue was purified by chromatography to afford thetitle compound MS (m/z): 399 (M+1)⁺.

Compounds 245-260

The following compounds 245-260 were prepared according to theprocedures of Compound 244 using the corresponding intermediates undersimilar conditions that will be recognized by one skilled in the art.

TABLE 4 Compound Structure LC/MS data 245

375 (M + 1)⁺ 246

347 (M + 1)⁺ 247

389 (M + 1)⁺ 248

372 (M + 1)⁺ 249

362 (M + 1)⁺ 250

356 (M + 1)⁺ 252

372 (M + 1)⁺ 253

361 (M + 1)⁺ 254

389 (M)⁺ 255

370 (M + 1)⁺ 256

370 (M + 1)⁺ 257

356 (M + 1)⁺ 258

356 (M + 1)⁺ 259

371 (M + 1)⁺ 260

337 (M + 1)⁺

Compound 261:N-(5-(1-methyl-1H-pyrazol-4-yl)-3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl)acetamide

N-(2,6-Dichloropyridin-4-yl)nitramide

2,6-Dichloropyridin-4-amine (3.0 g, 18 mmol) was carefully added toconcentrated sulfuric acid (20 mL). The mixture was cooled in an icebath, and fuming nitric acid (2.6 mL) was added dropwise via pipette.The mixture was warmed to room temperature and stirred for 1 h, thenpoured onto crushed ice, resulting in a white precipitate. The whiteprecipitate was collected by filtration, washed with cold water, anddried to afford the title compound (3.7 g), which was used for next stepwithout further purification.

2,6-Dichloro-3-nitropyridin-4-amine

N-(2,6-Dichloropyridin-4-yl)nitramide (3.7 g, 18 mmol) was added toconcentrated sulfuric acid (5 mL), and the reaction mixture was heatedat 60° C. for 30 mins After cooled to room temperature, the reactionmixture was poured onto crushed ice, and concentrated ammonium hydroxidewas added until the pH reached about 7. The precipitate was collected byfiltration, washed with ice cold water, and dried to afford the titlecompound (2.5 g). MS (m/z): 208 (M+1)^(r).

N-(2,6-Dichloro-3-nitropyridin-4-yl)acetamide

2,6-Dichloro-3-nitropyridin-4-amine (208 mg, 1 mmol) was added to aceticanhydride (2 mL), and the reaction mixture was refluxed overnight. Aftercooled to room temperature, the reaction mixture was basified withaqueous Na₂CO₃ until the pH was 8. The resulting mixture was thenextracted with CH₂Cl₂. The organic layer was separated, dried overNa₂SO₄, and concentrated to afford the title compound (240 mg), whichwas used for the next step without further purification. MS (m/z): 250(M+1)⁺.

N-(6-Chloro-3-nitro-2-(quinolin-6-ylmethylamino)pyridin-4-yl)acetamide

To a mixture of N-(2,6-dichloro-3-nitropyridin-4-yl)acetamide (240 mg,0.96 mmol) and quinolin-6-ylmethanamine (150 mg, 0.96 mmol) in CH3CN (10mL) was added Et₃N (0.5 mL). The reaction mixture was stirred at 80° C.for 1 h. After being cooled to room temperature, the mixture waspurified by chromatography on silica gel eluting with DCM/MeOH=50/1 toafford the title compound (220 mg). MS (m/z): 372 (M+1)⁺.

N-(3-Amino-6-chloro-2-(quinolin-6-ylmethylamino)pyridin-4-yl)acetamide

To a solution ofN-(6-chloro-3-nitro-2-(quinolin-6-ylmethylamino)pyridin-4-yl)acetamide(220 mg, 0.593 mmol) in methanol (5 mL) and CH₂Cl₂(5 mL) was added 10%catalytical amount Pd/C. The reaction mixture was stirred at roomtemperature under 1 atm of H₂ for 1 h, then filtered. The filtrate wasconcentrated to afford the title compound, which was used for the nextstep without further purification. MS (m/z): 342 (M+1)⁺.

N-(5-Chloro-3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl)acetamide

N-(3-amino-6-chloro-2-(quinolin-6-ylmethylamino)pyridin-4-yl)acetamidewas added to a solution of acetic acid (2 mL) and water (2 mL) at 0° C.,followed by the addition of NaNO₂ (180 mg, 2.6 mmol) in H₂O (0.2 mL).The reaction was stirred at 0° C. for 1 h, and then basified with 30%NaOH to pH=7. The resulting precipitate was collected by filtration toafford the title compound (80 mg), which was used for the next stepwithout further purification. MS (m/z): 353 (M+1)⁺.

N-(5-(1-Methyl-1H-pyrazol-4-yl)-3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl)acetamide

To a mixture ofN-(5-chloro-3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl)acetamide(80 mg, 0.227 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (50mg, 0.24 mmol) and Na₂CO₃ (48 mg, 0.25 mmol) in dioxane (10 mL) and H₂O(1 mL) under N2 was added Pd(dppf)Cl₂ (20 mg, 0.02 mmol). The reactionmixture was stirred at 100° C. under N₂ overnight. After cooled to roomtemperature, the reaction mixture was concentrated and purified bychromatography to afford the title compound (7 mg). MS: 400 (M+1)⁺.

Compound 262:5-(1-Methyl-1H-pyrazol-4-yl)-3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo-[4,5-b]pyridin-7-ol

6-Chloro-3-nitro-N2-(quinolin-6-ylmethyl)pyridine-2,4-diamine

To a mixture of 2,6-dichloro-3-nitropyridin-4-amine (624 mg, 3 mmol) andquinolin-6-ylmethanamine (316 mg, 2 mmol) in CH₃CN (10 mL) was addedEt₃N (0.5 mL). The reaction mixture was stirred at 80° C. for 1 h. Aftercooled to room temperature, the mixture was concentrated to afford thetitle compound (658 mg). MS (m/z): 330 (M+1)⁺.

6-(1-1H-pyrazol-4-yl)-3-nitro-N2-(quinolin-6-ylmethyl)pyridine-2,4-diamine

To a mixture of6-chloro-3-nitro-N2-(quinolin-6-ylmethyl)pyridine-2,4-diamine (658 mg, 2mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(500 mg, 2.4 mmol) and Na₂CO₃ (424 mg, 4 mmol) in dioxane (20 mL) andH₂O (2 mL) under N₂ was added Pd(dppf)Cl₂ (160 mg, 0.2 mmol). Thereaction mixture was stirred at 100° C. under N₂ overnight. After cooledto room temperature, the mixture was concentrated and purified bychromatography to afford the title compound (300 mg). MS (m/z): 376(M+1)⁺.

6-(1-Methyl-1H-pyrazol-4-yl)-3-nitro-2-(quinolin-6-ylmethylamino)pyridin-4-ol

To a mixture of6-(1-methyl-1H-pyrazol-4-yl)-3-nitro-N²-(quinolin-6-ylmethyl)pyridine-2,4-diamine(260 mg, 0.69 mmol) in HBF4 (5 mL) at 0° C. was added HNO₂ (96 mg, 1.4mmol) in H₂O (0.5 mL). The reaction mixture was stirred at 0° C.overnight, then basified with aqueous NaHCO₃ to pH=6-7. The resultingmixture was filtered. The filtrate was concentrated and purified bychromatography on silica gel to afford the title compound (200 mg). MS(m/z): 377 (M+1)⁺.

3-Amino-6-(1-methyl-1H-pyrazol-4-yl)-2-(quinolin-6-ylmethylamino)pyridin-4-ol

To a solution of6-(1-methyl-1H-pyrazol-4-yl)-3-nitro-N2-(quinolin-6-ylmethyl)pyridine-2,4-diamine(200 mg, 0.53 mmol) in methanol (10 mL) was added 10% Pd/C (20 mg, 0.1eq). The reaction mixture was stirred at room temperature under 1 atm ofH₂ for 2 h, then filtered. The filtrate was concentrated to afford thetitle compound (170 mg), which was used for the next step withoutfurther purification. MS (m/z): 347 (M+1)⁺.

5-(1-Methyl-1H-pyrazol-4-yl)-3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-7-ol

3-amino-6-(1-methyl-1H-pyrazol-4-yl)-2-(quinolin-6-ylmethylamino)pyridin-4-ol(170 mg, 0.49 mmol) was added to a solution of acetic acid (3 mL) andH₂O (3 mL) at 0° C., followed by the addition of NaNO₂ (69 mg, 10 mmol)in H₂O (0.3 mL). The reaction mixture was stirred at 0° C. for 1 h, thenbasified with aqueous 30% NaOH to pH=6-7 and purified by chromatographyto afford the title compound (120 mg). MS (m/z): 358 (M+1)⁺.

Compound 263:6-((7-Chloro-5-(1-methyl-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

5-(1-Methyl-1H-pyrazol-4-yl)-3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-7-ol(120 mg, 0.336 mmol) was dissolved in POCl₃ (2 ml). The reaction mixturewas stirred at 110° C. for 1 h. After cooled to 0° C., the mixture wasbasified with aqueous NaHCO₃ to pH=7, and extracted with EtOAc. Theorganic layer was separated, dried over anhydrous Na₂SO₄, concentrated,and purified by chromatography to afford the title compound (25 mg). MS:376 (M+1)⁺.

Compound 264:5-(1-Methyl-1H-pyrazol-4-yl)-3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo-[4,5-b]pyridin-7-amine

tert-Butyl 2,6-dichloro-3-nitropyridin-4-ylcarbamate

To a solution of 2,6-dichloro-3-nitropyridin-4-amine (832 mg. 4 mmol) inTHF (10 mL) was added DMAP (50 mg, 0.4 mmol) and (Boc)₂O (1.0 g, 4.6mmol) in that order. The reaction mixture was stirred at roomtemperature for 2 h, then concentrated. The residue was purified bychromatography on silica gel eluting with Pet/EtOAc=50/1 to afford thetitle compound (1.20 g).

tert-Butyl6-chloro-3-nitro-2-(quinolin-6-ylmethylamino)pyridin-4-ylcarbamate

A solution of tert-butyl 2,6-dichloro-3-nitropyridin-4-ylcarbamate (1.2g, 3.9 mmol) and quinolin-6-ylmethanamine (616 mg, 3.9 mmol) in CH₃CN(15 mL) and Et₃N (1 mL) was stirred at 80° C. for 1 h. After cooled toroom temperature, the mixture was concentrated. The residue was purifiedby chromatography to afford the title compound (1.60 g). MS (m/z): 430(M+1)⁺.

tert-Butyl6-(1-methyl-1H-pyrazol-4-yl)-3-nitro-2-(quinolin-6-ylmethylamino)pyridin-4-ylcarbamate

To a mixture of tert-butyl6-chloro-3-nitro-2-(quinolin-6-ylmethylamino)pyridin-4-ylcarbamate (860mg, 2 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(416 mg, 2 mmol) and Na₂CO₃ (424 mg, 4 mmol) in dioxane (20 mL) and H₂O(2 mL) under N₂ was added Pd(dppf)Cl₂ (163 mg, 0.2 mmol). The reactionwas stirred at 80° C. under N₂ overnight. After cooled to roomtemperature, the mixture was concentrated and purified by chromatographyto afford the title compound (950 mg). MS (m/z): 476 (M+1)⁺.

tert-Butyl3-amino-6-(1-methyl-1H-pyrazol-4-yl)-2-(quinolin-6-ylmethylamino)pyridin-4-ylcarbamate

To a solution of tert-butyl6-(1-methyl-1H-pyrazol-4-yl)-3-nitro-2-(quinolin-6-ylmethylamino)pyridin-4-ylcarbamate(950 mg, 2 mmol) in methanol (10 mL) was added 10% Pd/C (95 mg, 0.1 eq).The reaction was stirred at room temperature under 1 atm of H₂ for 1 h,then filtered. The filtrate was concentrated to afford the titlecompound (890 mg), which was used for the next step without furtherpurification. MS (m/z): 446 (M+1)⁺.

5-(1-Methyl-1H-pyrazol-4-yl)-3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-7-amine

tert-Butyl3-amino-6-(1-methyl-1H-pyrazol-4-yl)-2-(quinolin-6-ylmethylamino)pyridin-4-ylcarbamate(890 mg, 2 mmol) was added to a solution of acetic acid (5 mL) and water(5 mL) at 0° C., followed by the addition of NaNO₂ (300 mg, 4 mmol) inH₂O (0.5 mL). The reaction was stirred at 0° C. for 1 h, then basifiedwith 30% NaOH to pH=8. The resulting mixture was filtered to afford asolid. The solid was treated with TFA (3 mL), and then stirred at roomtemperature for another 0.5 h, before treated with aqueous Na₂CO₃ toadjust the pH to 8. The resulting mixture was purified by chromatographyto afford the title compound (190 mg). MS: 358 (M+1)⁺.

Compound 278:1-((3-Bromoimidazo[1,2-a]pyridin-6-yl)methyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine

To a solution of Compound 33 (10 mg, 0.03 mmol) in CHCl₃ (3 mL) wasadded NBS (5.4 mg, 0.031 mmol). The reaction mixture was stirred at roomtemperature overnight. The solvent was evaporated, and the residue waspurified by chromatography to afford the title compound (11 mg). MS(m/z): 411.7 (M+1)⁺.

Compound 300

Compound 300 was prepared with NCS according to the procedure ofCompound 278. MS (m/z): 365.9 (M+1)⁺.

Compound 306:2-(4-(1-((3-(Hydroxymethyl)imidazo[1,2-a]pyridin-6-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)-1H-pyrazol-1-yl)ethanol

To a solution of 306-a (60 mg, 0.13 mmol) (prepared according to theprocedure of Compound 1) in 0.1 mL of acetic acid were added sodiumacetate (39 mg, 0.48 mmol) and then formaldehyde (0.13 mL, 37% inwater). The mixture was stirred at 100° C. overnight. After cooled, themixture was adjusted to pH>7 with aqueous NaOH. The resultingprecipitate was collected and purified by chromatography to afford thetitle compound (10 mg). MS (m/z): 392.0 (M+H)⁺

Compound 307:6-((6-(1-Methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)-imidazo[1,2-a]pyridine-3-carbaldehyde

To a mixture of Compound 33 (33 mg, 0.1 mmol) in 0.2 mL of acetic acidand 0.4 mL of water was added hexamethylenetetramine (16 mg, 0.11 mmol).The mixture was stirred at 120° C. overnight. After cooled, the mixturewas adjusted to pH>7 with aqueous NaOH and purified by chromatography toafford the title compound (5 mg). MS (m/z): 360.0 (M+H)⁺.

Compound 311:2-(4-(1-(Pyrazolo[1,5-a]pyridin-5-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)-1H-pyrazol-1-yl)ethanol

To a solution of1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-6-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine311-a (10 mg, 0.022 mmol) (prepared according to the procedure ofCompound 1) in CHCl₃ was added NBS (4.4 mg, 0.025 mmol). The reactionmixture was stirred at rt for 1 h, then concentrated. The resultingresidue was dissolved in CHCl₃ (2 mL) and MeOH (2 mL), followed by theaddition of 6N HCl in MeOH. The resulting mixture was stirred for 30min, then treated with NH3.H2O to bring pH to 8. The mixture wasconcentrated and purified by prep-TLC to afford the title compound. MS(m/z): 439.9 (M+1)⁺.

Compound 312:5-((6-(1-(2-Hydroxyethyl)-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde

To a solution of1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-6-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine311-a (125 mg, 0.28 mmol) in AcOH/H₂O (2 mL/1 mL) was added HMTA (79 mg,0.56 mmol). The reaction mixture was stirred at 110° C. for 2 h, thentreated with NH₃.H₂O to bring pH to 8. The resulting mixture was thenconcentrated and purified by prep-TLC to afford the title compound (67mg). MS (m/z): 389.37 (M+1)⁺.

Compound 313:2-(4-(1-((3-(Hydroxymethyl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)-1H-pyrazol-1-yl)ethanol

To a solution of compound 312 (10 mg, 0.025 mmol) in MeOH was addedNaBH₄ (4 mg, 0.051 mmol). The reaction was stirred at room temperaturefor 1 h, then concentrated and purified by prep-TLC to afford the titlecompound.

Compound 318:1-(1-(3-(methoxymethyl)imidazo[1,2-a]pyridin-6-yl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine

Intermediate 318-a was prepared according to the procedure of Compound306 by using Compound 331.

To a mixture of(6-(1-(6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)ethyl)H-imidazo[1,2-a]pyridin-3-yl)methanol318-a (40 mg, 0.11 mmol) in 30 mL of THF was added sodium hydride (22mg, 0.53 mmol, 60% in mineral oil) at 0° C. The mixture was stirred at0° C. for 1 h, then iodomethane (60 mg, 0.43 mmol) was added. Themixture was stirred at room temperature overnight, then treated withsat. Na₂CO₃, then concentrated. The residue was diluted with water, andextracted with ethyl acetate. The combined organic layers were driedover Na₂SO₄, concentrated and purified by chromatography on silica gelto afford the title compound (30 mg) MS (m/z): 389.9 (M+H)⁺

Compounds 319 and 320

Compounds 319 and 320 were prepared according to the procedure ofCompound 327. Compound 319: MS: 388.9 (M+1)⁺; Compound 320 MS: 431(M+1)⁺

Compounds 321

Compound 321 was prepared according to the procedure of Compound 318starting from Compound 272. MS: 389.9 (M+1)⁺.

Compound 322

5-((6-Bromo-1H-[1,2,3]-triazolo[4,5-b]pyrazin-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde(322-b)

The title compound (Intermediate 322-b) was prepared according to theprocedure of Compound 307.

5-((6-(1-(2-(Tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde(322-c)

The title compound (Intermediate 322-c) was prepared from 322-baccording to the procedure of Compound 1.

5-((6-(1-(2-(Tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)methanol(332-d

The title compound (Intermediate 322-d) was prepared from 322-caccording to the procedure of Compound 313. MS (m/z): 476.1 (M+H)⁺.

1-((3-(Methoxymethyl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-6-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine(332-e)

The title compound (Intermediate 322-e) was prepared from 322-daccording to the procedure of Compound 318.

2-(4-(1-((3-(Methoxymethyl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)-1H-pyrazol-1-yl)ethanol(compound 322)

To a mixture of 322-e (40 mg, 0.082 mmol) in methanol (15 mL) was addeda solution of HCl in methanol (0.5 mL, 5 N). The mixture was stirred at0° C. for 1 h, then treated with ammonia to adjust pH to >7. Theresulting solution was concentrated and purified by chromatography toafford the title compound (15 mg).

Compounds 323

Compound 323 was prepared from compound 272 according to the procedureof Compound 318. MS: 403.9 (M+1)⁺

Compound 327:N-methyl-1-(6-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)imidazo[1,2-a]pyridin-3-yl)methanamine

To a mixture of compound 33 (50 mg, 0.15 mmol) in acetic acid (0.5 mL)were added ammonium chloride (61 mg, 0.9 mmol) and formaldehyde (61 mg,0.75 mmol, 37% in water). The mixture was stirred at 55° C. for 24 h.The reaction was treated with ammonia to adjust the pH to >7, thenconcentrated and purified by chromatography to afford the title compound(15 mg). MS (m/z): 374.8 (M+H)⁺.

Compound 330

N-(5-(1-(6-(1-Methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)ethyl)pyridin-2-yl)formamide(330-a)

To a solution of the compound 331 (1.0 g) in 100 mL of CH₂Cl₂ wasbubbled O₃ at −60-−70° C. for 30 mins, then N₂ for 10 mins. The reactionmixture was treated with Na₂SO₃ solution, and stirred for 10 mins. Theresulting mixture was extracted with CH₂Cl₂. The organic layer wasconcentrated and purified by chromatography to afford the title compoundas a solid (300 mg). MS (m/z): 322 (M+H)⁺.

5-(1-(6-(1-Methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)ethyl)pyridin-2-amine(Compound 330)

A solution of compound 330-a (300 mg) in 10 mL of HCl/CH₃OH was stirredovernight, then concentrated and basified with Na₂CO₃ solution. Theresulting mixture was purified by chromatography to afford the titlecompound as a solid, 155 mg.

Compound 77 and 78

The racemic Compound 332 (4 mg) was resolved by chiral HPLC to producethe optically pure enantiomers Compound 77 (0.7 mg) and 78 (1.1 mg)(HPLC conditions: Gilson system, Column: Dicel IA 4.6×250 mm; mobilephase: n-hexane/i-PrOH/DEA=70/30/0.1; flow rate, 1 mL/min; detector: UV254 nm). Compound 77 is the first eluent with at least 98% ee, MS (m/z):386 (M+1)⁺. Compound 78 is the second eluent with at least 98% ee, MS(m/z): 386 (M+1)⁺.

Compound 270 and 271

The racemic compound 331 (3 mg) was resolved by chiral HPLC to producethe optically pure enantiomers Compound 270 (0.9 mg) and 271 (1.1 mg).(HPLC conditions: Gilson system, column: Dicel IA 20×250 mm; mobilephase: EtOH/CH₃CN=9/1; flow rate=8 mL/min; detector: UV 254 nm),Compound 270 is the first eluent with at least 98% ee, MS (m/z): 346(M+1)⁺. and Compound 271 is the second eluent with 93% ee, MS (m/z): 346(M+1)⁺.

Compounds 314 and 315

The racemic compound 310 (5 mg) was resolved by chiral HPLC to produceoptically pure enantiomers Compound 314 (1.0 mg) and Compound 315 (1.9mg). (HPLC conditions: Gilson system, Column: Dicel IA 20×250 mm; Mobilephase: n-Hexane/i-PrOH/DEA=6/4/0.1; Flow rate: 8 ml/min; Detector: 254nm). Compound 314 is the first eluent with 95% ee, MS (m/z): 376 (M+1)⁺.Compound 315 is the second eluent with 80% ee, MS (m/z): 376 (M+1)⁺.

Compounds 324 and 325

Racemic Compound 318 (50 mg) was resolved by chiral HPLC to produceenantiomeic Compounds 324 (15 mg) and 325 (8 mg). (HPLC conditions:Gilson system; column: dicel IA, 20×250 mm IA; mobile phase:ethanol/methanol/DEA=70/30/0.1; detector: UV 254 nm). Compound 324 isthe first eluent with at least 98% ee, MS (m/z): 390 (M+1)⁺. Compound325 is the second eluent with at least 90% ee, MS (m/z): 390 (M+1)⁺.

Example 2 Inhibition of c-Met Kinase Activity Using Transcreener FPAssay

1. Reagents

Transcreenen™ KINASE Assay kit: Bellbrook Labs, 3003-10K;

Recombinant human Met: Invitrogen, PV3143;

Poly E4Y (substrate): Sigma, P0275; 5 mg/mL, dissolved in H₂O;

Assay buffer: 67 mM HEPES, 0.013% Triton X-100, 27 mM MgCl₂, 0.67 mMMnCl₂, 1.25 mM DTT, PH 7.4;

10 mM ATP: Invitrogene, PV3227;

500 mM EDTA: Invitrogene, 15575-038;

96 well black Greiner plate: Greiner, 675076.

2. Solution Preparation

Compound dilution: dilute test articles to 5 folds of the testingconcentration using 20% DMSO.

Prepare Enzyme/Substrate stock: dilute recombinant human c-Met and PolyE4Y in assay buffer to 0.5 μg/mL for c-Met, and 62.5 μg/mL for Poly E4Y.The mixture is kept on ice until use;

Prepare ATP Diluent: dilute 10 mM ATP stock to 25 μM with assay buffer;

Prepare ADP Diluent: dilute 500 μM ADP stock to 25 μM with assay buffer;

Prepare ATP standard curve stock as following:

Column ADP diluent (uL) ATP diluent (uL) 1 50 0 2 25 25 3 10 40 4 5 45 55 95 6 5 195 7 5 495 8 4 496 9 3 497 10 2 498 11 1 499 12 1 999

3. Enzymatic reaction: in 96-well reaction plate

Add 5 μL of test article or 5 μL of 20% DMSO or 5 μL of 500 mM EDTA;

Add 10 μL of Enzyme/Substrate stock;

Add 10 μL of ATP Diluent to begin the enzyme reaction and mix on plateshaker;

Add 5 μL of 20% DMSO, 10 μL of assay buffer and 10 μL of ATP standardcurve stock into standard curve wells;

Gently shake at 28° C. for 45 min.

4. Stop Reaction and Detect ADP

Prepare Detection Mix: According to the procedures described in theAssay kit, Alexa633 tracer, ADP antibody and stop & detect buffer wereadded into H₂O and mixed thoroughly.

Prepare Tracer Only control: According to the procedures described inthe Assay kit, ADP Alexa633 tracer and stop & detect buffer were addedto H₂O and mixed throughly.

Prepare No Tracer control: According to the procedures described in theAssay kit, the stop & detect buffer was diluted with H₂O;

Add 25 μL of detection mix, Tracer Only control and No Tracer controlinto corresponding wells, respectively;

The reaction plate was gently shaken at 28° C. for 1 h;

Florescence polarization (FP) was measured on TECAN F500. Excitationwavelength: 610 nm, Emission wavelength: 670 nm.

5. Data Analysis

${{Inhibition}\mspace{14mu}(\%)} = {100 - {\frac{{Compound}\mspace{14mu}{{well}\mspace{14mu}\lbrack{ADP}\rbrack}}{{Positive}\mspace{14mu}{control}\mspace{14mu}{{well}\mspace{14mu}\lbrack{ADP}\rbrack}} \times 100}}$Where:Compound well [ADP] represents the ADP concentration of the compoundwell. Positive control well [ADP] represents the ADP concentration ofthe 20% DMSO well. Conversion of mP value to ADP concentration is basedon the formula which is determined by standard curve. Measurement of mPvalue follows the suggestion of the instructions provided by BellBrookLabs (www.bellbrooklabs.com).IC₅₀: Calculated Using XL-Fit 2.0 Software.IC₅₀ values of compounds 7, 8, 11, 12, 16, 19, 20, 25, 33, 34, 35, 36,42, 43, 44, 45, 47, 48, 49, 50, 56, 57, 77, 127, 128, 129, 153, 156,158, 161, 163, 169, 190, 192, 193, 195, 197, 198, 203, 207, 210, 212,220, 222, 223, 224, 225, 227, 228, 229, 230, 254, 265, 269, 270, 278,279, 280, 300, 301, 303, 308, 309, 314, 318, 325, 328, 332, 1, 13, 14,15, 21, 24, 26, 27, 46, 51, 52, 54, 58, 59, 61, 62, 63, 65, 70, 72, 76,81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 95, 97, 102, 104, 111, 112,113, 115, 117, 130, 131, 132, 133, 134, 135, 136, 137, 140, 141, 144,145, 146, 147, 150, 152, 155, 157, 160, 162, 164, 165, 166, 168, 172,173, 176, 177, 179, 180, 182, 183, 185, 186, 188, 189, 191, 194, 196,199, 200, 202, 213, 214, 215, 217, 218, 221, 226, 235, 237, 238, 239,240, 245, 246, 248, 250, 252, 253, 255, 258, 259, 266, 267, 268, 271,272, 274, 275, 276, 277, 281, 282, 283, 287, 290, 295, 298, 302, 304,305, 306, 307, 310, 311, 312, 313, 315, 319, 321, 322, 323, 324, 326,327, 329, 331 are in the range of 0.001 to less than 0.1 uM.IC₅₀ values of compounds 2, 5, 6, 9, 17, 18, 22, 23, 28, 30, 37, 38, 41,53, 55, 64, 66, 71, 73, 74, 78, 79, 80, 92, 93, 94, 96, 98, 99, 100,101, 103, 105, 107, 108, 109, 110, 116, 118, 119, 120, 121, 122, 123,126, 138, 142, 143, 154, 170, 174, 181, 187, 201, 204, 205, 206, 208,209, 216, 219, 231, 234, 236, 241, 244, 247, 249, 257, 260, 261, 263,273, 284, 285, 286, 288, 289, 292, 293, 294, 296, 299, 316, 317, 320,are from 0.1 uM to less than 1 uM.

What is claimed:
 1. A compound of formula 1:

or a pharmaceutically acceptable salt thereof wherein X is N, Y isabsent and R¹ is a fused bicyclic heteroaryl selected from:

optionally substituted with one or more groups selected from halo, —CF₃,—CF₂H, cycloalkyl, —C(O)R¹¹, —C(O)OR¹¹, —CN, —C(O)NR¹³R¹⁴, —NR¹³R¹⁴,—NR¹³C(O)R¹¹, —NR¹³S(O)_(n)R¹², —NR¹³S(O)_(n)NR¹³R¹⁴, —NR¹³C(O)OR¹²,—NR¹³C(O)NR¹³R¹⁴, —NO₂, —S(O)_(n)R¹², —S(O)_(n)NR¹³R¹⁴, heterocycle,heteroaryl, aryl, alkenyl, alkynyl, lower alkyl, lower alkyl substitutedwith hydroxy, lower alkyl substituted with lower alkoxy, lower alkylsubstituted with —NR¹³R¹⁴, and lower alkyl substituted with heterocycle;R² and R³ are independently selected from hydrogen, and alkyl, or R² andR³, together with the carbon to which they are attached, form a ringchosen from 3- to 7-membered cycloalkyl and 3- to 7-memberedheterocycle; R⁴ is selected from halo, alkyl, cycloalkyl, heterocycle,aryl and heteroaryl, each of which, except for halo, is optionallysubstituted with one or more groups selected from: (i) lower alkyloptionally substituted with one or more groups selected from hydroxy,lower alkoxy, cyano, halo, —C(O)OR¹¹, —C(O)NR¹³R¹⁴, —NR¹³R¹⁴, —OC(O)R¹¹,—NR¹³C(O)R¹¹, —NR¹³S(O)_(n)R¹², —NR¹³S(O)_(n)NR¹³R¹⁴, —NR¹³C(O)OR¹², and—NR¹³C(O)NR¹³R¹⁴; (ii) lower alkoxy optionally substituted with one ormore groups selected from halo, hydroxy, and lower alkoxy; (iii)cycloalkoxy optionally substituted with one or more groups selected fromhalo, hydroxy, and lower alkoxy; (iv) heterocycloalkoxy optionallysubstituted with one or more groups selected from halo, hydroxy, andlower alkoxy; (v) heterocycle optionally substituted with one or moregroups selected from lower alkyl, halo, hydroxy, and lower alkoxy; (vi)heteroaryloxy optionally substituted with one or more groups selectedfrom lower alkyl, halo, hydroxy, and lower alkoxy; (viii) aryloptionally substituted with one or more groups selected from loweralkyl, halo, hydroxy, and lower alkoxy; (ix) heteroaryl optionallysubstituted with one or more groups selected from lower alkyl, halo,hydroxy, and lower alkoxy; (x) halo; (xi) cyano; (xii) —C(O)R¹¹; (xiii)—C(O)OR¹¹; (xiv) —NR¹³R¹⁴; (xv) —NR¹³C(O)R¹¹; (xvi) —NR¹³S(O)_(n)R¹²;(xvii) —NR¹³S(O)_(n)NR¹³R¹⁴; (xviii) —NR¹³C(O)OR¹²; (xix)—NR¹³C(O)NR¹³R¹⁴; (xx) —C(O)NR¹³R¹⁴, (xxi) —S(O)_(n)R¹²; and (xxii)—S(O)_(n)NR¹³R¹⁴; R⁵ is selected from hydrogen, halo, OH, NH₂, CF₃,—CF₂H, alkyl, alkenyl, and alkynyl; each n is independently 0, 1, or 2;R¹¹, R¹², R¹³, and R¹⁴ are independently selected from hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocycle, each ofwhich except for hydrogen, is optionally substituted with one or moregroups selected from halo, lower alkyl, hydroxy, and lower alkoxy, orR¹³ and R¹⁴, with the nitrogen to which they are attached, combine toform a heterocycle ring, which is optionally substituted with one ormore groups selected from halo, lower alkyl, hydroxy, and lower alkoxyand further optionally includes one or two additional heteroatoms in theheterocycle ring wherein the one or two additional heteroatoms areselected from —O—, —S—, and —N(R¹⁵)—; and R¹⁵ is selected from hydrogen,lower alkyl, —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR¹³R¹⁴, —S(O)_(n)R¹², and—S(O)_(n)NR¹³R¹⁴; provided that: when R² is hydrogen or methyl and R³and R⁵ are hydrogen, then R¹ is not 3-quinazolin-6-yl.
 2. The compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof,wherein R¹ is a ring system selected from:


3. The compound according to claim 1, or a pharmaceutically acceptablesalt thereof, wherein R² and R³ are independently selected from hydrogenand C₁-C₆ alkyl or R² and R³, together with the carbon to which they areattached, form a 3-membered cycloalkyl.
 4. The compound according toclaim 1, or a pharmaceutically acceptable salt thereof, wherein R⁵ ishydrogen.
 5. The compound according to claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R⁴ is aryl optionally substituted withone or more groups selected from: (i) lower alkyl optionally substitutedwith one or more groups selected from hydroxy, lower alkoxy, cyano,halo, —C(O)OR¹¹, —C(O)NR¹³R¹⁴, —NR¹³R¹⁴, —OC(O)R¹¹, —NR¹³C(O)R¹¹,—NR¹³S(O)_(n)R¹², —NR¹³S(O)_(n)NR¹³R¹⁴, —NR¹³C(O)OR¹², and—NR¹³C(O)NR¹³R¹; (ii) lower alkoxy optionally substituted with one ormore groups selected from halo, hydroxy, and lower alkoxy; (iii)heterocycle optionally substituted with one or more groups selected fromlower alkyl, halo, hydroxy, and lower alkoxy; (iv) heteroaryloxyoptionally substituted with one or more groups selected from loweralkyl, halo, hydroxy, and lower alkoxy; (v) aryl optionally substitutedwith one or more groups selected from lower alkyl, halo, hydroxy, andlower alkoxy; (vi) heteroaryl optionally substituted with one or moregroups selected from lower alkyl, halo, hydroxy, and lower alkoxy; (vii)halo; (viii) cyano; (ix) —C(O)R¹¹; (x) —C(O)OR¹¹; (xi) —NR¹³R¹⁴; (xii)—NR¹³C(O)R¹¹; (xiii) —NR¹³S(O)_(n)R¹²; (xiv) —NR¹³S(O)_(n)NR¹³R¹⁴; (xv)—NR¹³C(O)OR¹²; (xvi) —NR¹³C(O)NR¹³R¹⁴; (xvii) —C(O)NR¹³R¹⁴; (xviii)—S(O)_(n)R¹²; and (xix) —S(O)_(n)NR¹³R¹⁴.
 6. The compound according toclaim 1, or a pharmaceutically acceptable salt thereof, wherein R⁴ isheterocycle optionally substituted with one or more groups selectedfrom: (i) lower alkyl optionally substituted with one or more groupsselected from hydroxy, lower alkoxy, cyano, halo, —C(O)OR¹¹,—C(O)NR¹³R¹⁴, —NR¹³R¹⁴, —OC(O)R¹¹, —NR¹³C(O)R¹¹, —NR¹³S(O)_(n)R¹²,—NR¹³S(O)_(n)NR¹³R¹⁴, —NR¹³C(O)OR¹², and —NR¹³C(O)NR¹³R¹⁴; (ii) loweralkoxy optionally substituted with one or more groups selected fromhalo, hydroxy, and lower alkoxy; (iii) heterocycle optionallysubstituted with one or more groups selected from lower alkyl, halo,hydroxy, and lower alkoxy; (iv) halo; (v) cyano; (vi) C(O)R¹¹; (vii)—C(O)OR¹¹; (viii) —NR¹³R¹⁴; (ix) —NR¹³C(O)R¹¹; (x) —NR¹³S(O)_(n)R¹²;(xi) —NR¹³S(O)_(n)NR¹³R¹⁴; (xii) —NR¹³C(O)OR¹²; (xiii) —NR¹³C(O)NR¹³R¹⁴;(xi) —C(O)NR¹³R¹⁴; (xii) —S(O)_(n)R¹²; and (xiii) —S(O)_(n)NR¹³R¹⁴. 7.The compound according to claim 6, or a pharmaceutically acceptable saltthereof, wherein R⁴ is selected from pyrrolidin-1-yl, piperidin-1-yl,tetrahydro-2H-pyran-4-yl, morpholin-4-yl, and6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl, each of which is optionallysubstituted with one or more groups selected from: (i) lower alkyloptionally substituted with one or more groups selected from hydroxy,lower alkoxy, cyano, halo, —C(O)OR¹¹, —C(O)NR¹³R¹⁴, —NR¹³R¹⁴, —OC(O)R¹¹,—NR¹³C(O)R¹¹, —NR¹³S(O)_(n)R¹², —NR¹³S(O)_(n)NR¹³R¹⁴, —NR¹³C(O)OR¹², and—NR¹³C(O)NR¹³R¹⁴; (ii) lower alkoxy optionally substituted with one ormore groups selected from halo, hydroxy, and lower alkoxy; (iii)heterocycle optionally substituted with one or more groups selected fromlower alkyl, halo, hydroxy, and lower alkoxy; (iv) halo; (v) cyano; (vi)C(O)R¹¹; (vii) —C(O)OR¹¹; (viii) —NR¹³R¹⁴; (ix) —NR¹³C(O)R¹¹; (x)—NR¹³S(O)_(n)R¹²; (xi) —NR¹³S(O)_(n)NR¹³R¹⁴; (xii) —NR¹³C(O)OR¹²; (xiii)—NR¹³C(O)NR¹³R¹⁴; (xiv) —C(O)NR¹³R¹⁴; (xv) —S(O)_(n)R¹²; and (xvi)—S(O)_(n)NR¹³R¹⁴.
 8. The compound according to claim 1, or apharmaceutically acceptable salt thereof, wherein R⁴ is heteroaryloptionally substituted with one or more groups selected from: (i) loweralkyl optionally substituted with one or more groups selected fromhydroxy, lower alkoxy, cyano, halo, —C(O)OR¹¹, —C(O)NR¹³R¹⁴, —NR¹³R¹⁴,—OC(O)R¹¹, —NR¹³C(O)R¹¹, —NR¹³S(O)_(n)R¹², —NR¹³S(O)_(n)NR¹³R¹⁴,—NR¹³C(O)OR¹², and —NR¹³C(O)NR¹³R¹⁴; (ii) lower alkoxy optionallysubstituted with one or more groups selected from halo, hydroxy, andlower alkoxy; (iii) heterocycle optionally substituted with one or moregroups selected from lower alkyl, halo, hydroxy, and lower alkoxy; (iv)halo; (v) cyano; (vi) —C(O)R¹¹; (vii) —C(O)OR¹¹; (viii) —NR¹³R¹⁴; (ix)—NR¹³C(O)R¹¹; (x) —NR¹³S(O)_(n)R¹²; (xi) —NR¹³S(O)_(n)NR¹³R¹⁴; (xii)—NR¹³C(O)OR¹²; (xiii) —NR¹³C(O)NR¹³R¹⁴; (xiv) —C(O)NR¹³R¹⁴; (xv)—S(O)_(n)R¹²; and (xvi) —S(O)_(n)NR¹³R¹⁴.
 9. The compound according toclaim 8, or a pharmaceutically acceptable salt thereof, wherein R⁴ isselected from 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl,1H-imidazol-1-yl, 1H-imidazol-4-yl, oxazol-2-yl, thiazol-2-yl,isoxazol-3-yl, isoxazol-5-yl, 1H-pyrrol-2-yl, 1H-pyrrol-3-yl,thiophen-2-yl, thiophen-3-yl, pyridin-2-yl, pyridin-3-yl, andpyridin-4-yl, each of which is optionally substituted with one or moregroups selected from: (i) lower alkyl optionally substituted with one ormore groups selected from hydroxy, lower alkoxy, cyano, halo, —C(O)OR¹¹,—C(O)NR¹³R¹⁴, —NR¹³R¹⁴, —OC(O)R¹¹, —NR¹³C(O)R¹¹, —NR¹³S(O)_(n)R¹²,—NR¹³S(O)_(n)NR¹³R¹⁴, —NR¹³C(O)OR¹², and —NR¹³C(O)NR¹³R¹⁴; (ii) loweralkoxy optionally substituted with one or more groups selected fromhalo, hydroxy, and lower alkoxy; (iii) heterocycle optionallysubstituted with one or more groups selected from lower alkyl, halo,hydroxy, and lower alkoxy; (iv) halo; (v) cyano; (vi) C(O)R¹¹; (vii)—C(O)OR¹¹; (vii) —NR¹³R¹⁴; (viii) —NR¹³C(O)R¹¹; (ix) —NR¹³S(O)_(n)R¹²;(x) —NR¹³S(O)_(n)NR¹³R¹⁴; (xi) —NR¹³C(O)OR¹²; (xii) —NR¹³C(O)NR¹³R¹⁴;(xiii) —C(O)NR¹³R¹⁴; (xiv) —S(O)_(n)R¹²; and (xv) —S(O)_(n)NR¹³R¹⁴. 10.The compound according to claim 1 of Formula:

enantiomers thereof, or a pharmaceutically acceptable salt thereof. 11.The compound of formula 1 as claimed in claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is a ring system selected from:

wherein each of said ring systems is optionally substituted with one ormore groups selected from halo, CF₃, —CF₂H, cycloalkyl, —C(O)R¹¹,C(O)OR¹¹, —CN, —C(O)NR¹³R¹⁴, —NR¹³R¹⁴, —NR¹³C(O)R¹¹, —NR¹³S(O)_(n)R¹²,—NR¹³S(O)_(n)NR¹³R¹⁴, —NR¹³C(O)OR¹², —NR¹³C(O)NR¹³R¹⁴, —NO₂,—S(O)_(n)R¹², —S(O)_(n)NR¹³R¹⁴, heterocycle, heteroaryl, aryl, alkenyl,alkynyl, lower alkyl, lower alkyl substituted with hydroxy, lower alkylsubstituted with lower alkoxy, lower alkyl substituted with —NR¹³R¹⁴,and lower alkyl substituted with heterocycle.
 12. The compound offormula 1 as claimed in claim 1, or a pharmaceutically acceptable saltthereof, wherein R¹ is a ring system selected from


13. The compound of formula 1 as claimed in claim 1, or apharmaceutically acceptable salt thereof, wherein R¹ is


14. The compound of formula 1 as claimed in claim 1, or apharmaceutically acceptable salt thereof, wherein R² is hydrogen and R³is selected from hydrogen and methyl.
 15. The compound of formula 1 asclaimed in claim 1, or a pharmaceutically acceptable salt there which isselected from:


16. The compound of formula 1 as claimed in claim 1, or apharmaceutically acceptable salt thereof, which is selected from:


17. A composition comprising a compound according to claim 1, or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.